Abstract
Brain neurons play a crucial role to maintain organism health in response to macro/micro-environmental biophysical and biochemical cues, and their dysfunction and death drive aging and diseases. However, cellular mechanisms controlling neuronal health are incompletely understood. Drosophila has proven a paramount model to understand fundamental pathways of tissue development, homeostasis, and cell death in health and disease. Among these pathways, the regulation of nuclear structure and function, including genome organization, RNA synthesis and processing, DNA damage repair, and nucleocytoplasmic transport, has been shown to play a major role. In this regulation, the nucleoskeleton, a meshwork of type A/C and B Lamin proteins, provides an interface between the cytoskeleton and chromatin, controlling (epi)genome dynamics and nucleocytoplasmic compartmentalization, also by interacting with the inner nuclear membrane and pore complexes. In postmitotic neurons, LaminB is the major nucleoskeletal component. In this Review, I focus on the key role of nuclear LaminB dynamics in neuronal homeostasis in aging and cell death, highlighting the power of Drosophila models to uncover the underlying fundamental mechanisms. In this context, I spotlight that the regulation of nuclear LaminB structure and function is emerging as a stress-integration gatekeeper controlling neuronal response to macro/micro-environmental biophysical and biochemical cues, which maintains neuronal health, and whose impairment drives neuronal aging and non-apoptotic cell death in neurodegenerative diseases.
Graphical Abstract
Introduction
Brain neurons play a crucial role to systemically control tissue function in response to macro- and micro-environmental biophysical and biochemical cues, and their dysfunction and death drive aging and diseases (Schmid et al., 2022; Schmid et al., 2024; Tokizane et al., 2024; Tokizane and Imai, 2025). Thus, maintenance of brain neurons health is critical for organism healthspan and longevity (Satoh et al., 2013; Zhang et al., 2013; Zullo et al., 2019; Oh et al., 2025). Yet the key cellular mechanisms controlling this maintenance are incompletely understood, and advancing their knowledge is essential to promote human health.
Drosophila has proven to be a paramount model to understand evolutionarily conserved pathways of tissue development, homeostasis, and cell death in health and disease (Verheyen, 2022). Paradigmatic examples include fundamental principles of genetic information, embryo- and organo-genesis, innate immunity (), circadian clocks (Patke et al., 2020), tissue growth and tumor suppression (Khan and Rusan, 2024), cell competition (), cell death and apoptosis-induced proliferation (; Yacobi-Sharon et al., 2013; Mollereau et al., 2014; Napoletano et al., 2017; Steller, 2026), nutrient sensing, stem cells, aging and longevity, and signaling cascades (; ; ; ).
Within eukaryotic cells, the nucleus is essential for the control of cell function, dynamics and death in tissue development and homeostasis in health and disease. This critically involves the regulation of nuclear structure and function, including genome organization and stability, epigenetic modifications, RNA synthesis and processing, DNA damage repair pathways, and nucleocytoplasmic compartmentalization and transport (Liu and Hetzer, 2022; ; Ho et al., 2026; Yücel and Gladyshev, 2026). In this regulation, a pivotal role is played by the nuclear envelope (NE), a complex and dynamic interface formed by the nuclear double membrane, nuclear pores and the nucleoskeleton. In particular, the nucleoskeleton is composed by intermediate-filament Lamin proteins of A/C and B types and provides a structural bridge between the cytoskeleton and chromatin, through the Linker of nucleoskeleton and cytoskeleton (LINC) protein complex, and together with the nuclear membrane and pores controls nucleocytoplasmic compartmentalization and transport (; Raab et al., 2016; ; Karoutas and Akhtar, 2021). In turn, the cytoskeleton is linked with the extracellular matrix (ECM), via cell adhesion structures (Kirby and Lammerding, 2018; Kalukula et al., 2022). Thanks to this organization, the nucleoskeleton crucially mediates the sensing and transduction of both biochemical and biophysical intra- and extra-cellular signals, controlling adaptive changes in the genome organization and function and cellular responses. Alterations in NE components have been shown to contribute to different diseases, including rare nuclear envelopathies caused by germline mutations, such as laminopathies, which include, for example, Hutchinson-Gilford progeria syndrome and Emery–Dreifuss muscular dystrophy caused by LaminA mutations (; ; Li et al., 2016; Wong et al., 2022).
In postmitotic neurons, LaminB is the major nucleoskeletal component (Jung et al., 2012). In this Review, I spotlight the emerging role of LaminB regulation in neuronal homeostasis in aging and cell death in neurodegenerative diseases, highlighting the power of Drosophila models to uncover the underlying fundamental mechanisms.
Hallmarks of neuronal health
As a framework to understand the determinants of neuronal health, I propose to apply the definition of key organizational and dynamic features that maintain physiology, and whose impairment drives pathology, which have been conceptualized as “Hallmarks of Health” interplaying at the organism, tissue, cellular, organelle and molecular levels (López-Otín and Kroemer, 2021). These hallmarks include spatial compartmentalization (integrity of barriers and perturbations containment), maintenance of homeostasis (recycling/turnover, integration of circuitries, rhythmic oscillations), and stress response regulation (resilience, hormesis, repair and regeneration).
The spatiotemporal trajectory of some of these features is particularly critical in postmitotic neurons, which are long lived and thus vulnerable to accumulation of unrepaired damage over time. For instance, neuronal function is highly sensitive to the maintenance and repair of barriers and containment of local perturbations, at the level of the NE, membranes of organelles such as mitochondria and lysosomes, axonal and dendritic compartments, integrity, fluidity and excitability of plasma membrane, and precise control of nucleocytoplasmic transport (Mattson and Arumugam, 2018; Kampmann, 2024; Wu et al., 2025; Radulovic et al., 2026). Failure of this compartmentalization can lead to leakage of nuclear and mitochondrial DNA into cytoplasm, senescence, mitochondrial and lysosomal membrane permeabilization, alterations in the magnitude, duration, location and temporal pattern of ion fluxes, in axonal transport, RNA localization and synaptic function, and disruption of energy homeostasis, leading to neuronal dysfunction and degeneration (; ; Nagano and Araki, 2021; ).
Furthermore, neuronal homeostasis is highly dependent on: integration of circuitries, including transcriptional and epigenetic networks regulating cell identity, RNA-processing/quality control and local-translation networks, organelle communication, proteostasis and metabolic networks, calcium and redox signaling, inter-organellar contact sites (e.g., nucleus-ER/mitochondria), synaptic plasticity and excitation-inhibition balance (Giandomenico et al., 2022); rhythmic oscillations aligning neuronal output with environmental demand, including molecular clocks controlling gene expression and neuroendocrine function and mitochondrial dynamics (Tseng et al., 2023; Zhu and Cohen, 2023); molecular recycling/turnover, involving molecular chaperones, ubiquitin-proteasome system activity, autophagy, mitophagy, and lysosomal clearance, which continuously remove damaged proteins and organelles (; Kim et al., 2022; Nixon and Rubinsztein, 2024).
Also, a key role in neuronal stress response is played by resilience, hormesis and repair pathways at the level of organelles and molecules, involving regulation of genome stability, gene expression and activity-dependent transcription, integrated-stress and unfolded protein responses, antioxidant programs, DNA-damage sensing and repair, mechano-response, and energy homeostasis (; Ho-Tieng et al., 2025; Jimenez-Blasco et al., 2026; Smith et al., 2026). Mild challenges can induce hormetic protection, whereas chronic proteotoxic, oxidative, metabolic or mechanical stress converts adaptive signaling into dysfunction (; Hetz et al., 2020). For instance, impairment of DNA repair, chromatin maintenance and RNA processing promote age-dependent neuronal decline and disease-associated protein aggregation (Konopka and Atkin, 2022; ). When resilience is exceeded, regulated cell death types can be activated including different non-apoptotic pathways such as regulated necrosis, ferroptosis and autophagy-dependent death (Napoletano et al., 2019; ; Lei et al., 2025).
Notably, Drosophila has been a key model to uncover the fundamental mechanisms of these processes and how their disruption drives neuronal aging and neurodegenerative diseases. These pathways include, for example (epi)genome and nuclear dynamics (Ulianov et al., 2019; Mengistu et al., 2026), the role of autophagy in stress response (Robin et al., 2019), the regulation of apoptotic and alternative cell death modalities (; Oyston et al., 2018), and pathways of neuro-inflammaging (Khor and Cai, 2020).
Bassed on this framework I propose to categorize a set of “Hallmarks of Neuronal Health”, including integrity, repair and long-term maintenance of cell body, axon, dendrite and envelopes of organelles; long-term maintenance of organelle and molecule recycling/turnover, cell identity, bioenergetic competence and organelle and molecule repair; aligning neuronal output with environmental demand; adaptive and activity-dependent structural plasticity (Table 1). In this context, the regulation of nuclear structure and function, and particularly of NE compartmentalization, integrity and chromatin dynamics, stands as a central hub involved in the interplay among all the hallmarks at the cellular, organelle and molecular levels.
TABLE 1
| Proposed Hallmarks of Neuronal Health | References | Mapping on the hallmarks of health (López-Otín and Kroemer, 2021) |
|---|---|---|
| 1. Integrity and repair of cell body, axon, dendrite and organelle envelope components | (Mattson and Arumugam, 2018; Kampmann, 2024; Wu et al., 2025; Radulovic et al., 2026; ; ; Nagano and Araki, 2021; ) | spatial compartmentalization |
| 2. Long-term maintenance of Cell axon, dendrite and organelle shape and polarization | ||
| 3. Long-term maintenance of organelle and molecule recycling/turnover | (Giandomenico et al., 2022; Tseng et al., 2023; Zhu and Cohen, 2023; ; Kim et al., 2022; Nixon and Rubinsztein, 2024) | maintenance of homeostasis |
| 4. Long-term maintenance of cell identity | ||
| 5. Aligning neuronal output with environmental demand | ||
| 6. Long-term maintenance of bioenergetic competence | (; Ho-Tieng et al., 2025; Jimenez-Blasco et al., 2026; Smith et al., 2026; ; Hetz et al., 2020; Konopka and Atkin, 2022; ; Napoletano et al., 2019; ; Lei et al., 2025) | stress response regulation |
| 7. Adaptive and activity-dependent structural plasticity | ||
| 8. Long-term maintenance of organelle and molecule repair |
Proposed hallmarks of neuronal health.
LaminB controls nuclear compartmentalization and integrity in neurons
LaminB proteins are ubiquitous nucleoskeletal components anchored to the inner nuclear membrane (INM) through farnesylation, forming a meshwork with LaminA/C proteins. Mammals express two main LaminB proteins encoded by different genes (LMNB1/2) with partially redundant functions (; Lee et al., 2014), while Drosophila expresses a single LaminB ortholog dubbed LaminDm0 (also known as Lam or LamB) (Odell and Lammerding, 2023). The LaminB meshwork dynamically interacts with chromatin and RNA binding proteins at the inner nuclear periphery, and with transmembrane proteins and component of the nuclear pores at the interface with the INM (; Liu and Hetzer, 2022). INM proteins interacting with LaminB include Lamin-associated polypeptide (LAP)-Emerin (EMD)-MAN1/LEMD3 domain family proteins (LEM), such as LAP2/TMPO and LEMD2, as well as LaminB receptor (LBR) and Sad1/UNC-84 (SUN)-domain proteins (Sosa et al., 2012; ). SUN proteins bind the outer nuclear transmembrane Klarsicht/ANC-1/Syne homology (KASH)-domain Nesprin proteins in the intermembrane space, forming the LINC complex, which in turn bind cytoskeletal fibers, such as F-Actin (Kirby and Lammerding, 2018). Thanks to this organization, the LaminB meshwork plays a key role for the function of the NE as a dynamic physical barrier maintaining nuclear compartmentalization, shape and physical properties, in response to both biochemical and mechanical stimuli generated intracellularly and from the ECM (Lenz-Böhme et al., 1997; Osouda et al., 2005; Stiekema et al., 2022).
In neurons, challenges that disrupt LaminB structure, such as physical constraints during migration and mechanical load associated with traumatic and proteotoxic stress, can therefore compromise nuclear shape and compartmentalization (Koufi et al., 2023). This can cause nuclear deformation that impact chromatin organization, genome integrity (due, for example, to permeation to nucleases and impairment of repair factors), alteration of RNA processing and transport, and cytoplasmic leakage of nuclear DNA and RNA activating sensors that trigger innate immunity and pro-inflammatory pathways, such as cGAS-STING and RIG-I (Kalukula et al., 2022). To cope with these challenges, LaminB structure is maintained by transcriptional and post-transcriptional regulation of its protein levels by different factors (e.g., YAP) (Sladitschek-Martens et al., 2022), post-translational modifications (PTMs) including phosphorylation, methylation and acetylation, and cooperation with repair pathways that surveille and seal ruptures in the nuclear membrane, involving LEM-Barrier-to-autointegration factor (BAF)-ESCRT-III protein complexes (Halfmann et al., 2019; ). Deregulation of this maintenance contributes to the pathogenesis of different neurological diseases, including neurodevelopmental disorders caused by LaminB point mutations, such as rare forms of microcephaly (; Parry et al., 2021). Furthermore, reduction of LaminB protein levels is associated with neuronal aging and degeneration in diseases (; Koufi et al., 2023) and cellular senescence (Lv et al., 2024; Sbriz et al., 2025). Also, LaminB alterations deregulate nuclear pore structure and function and thus nucleocytoplasmic transport, compromising nuclear compartmentalization (Liu and Hetzer, 2022).
The main components and the organization of the NE, including the LEM-domain proteins Otefin and Bocksbeutel, LBR, Klaroid and Spag4 SUN proteins, Msp-300/Nesprin, and nucleoporins, are conserved in Drosophila, which has proven to be an instrumental model to uncover fundamental structural functions of LaminB in neuronal health. For instance, LaminB knockdown in postmitotic neurons was shown to cause neurodegeneration and reduction of lifespan and locomotor ability in aging flies (Oyston et al., 2018). Also, in Drosophila models of tauopathies expressing dysfunctional and mutated form of the human microtubule-binding protein Tau (MAPT), mechanical load due to hyper-polymerization of Actin fibers, impinging on the nucleus through the LINC complex, was shown to cause nuclear LaminB deformation, with toxic accumulation of RNA within invaginations (Frost et al., 2016; ).
Together, this evidence highlights the key structural role of LaminB dynamic in neurons, underscoring the power of Drosophila to understand the underlying fundamental mechanisms (Figure 1).
FIGURE 1
LaminB regulation determines neuronal homeostasis and death in response to stress
Emerging evidence indicates that regulation of LaminB, in addition to its structural role in maintaining nuclear compartmentalization, is also central for brain neuron homeostasis in response to stress, by controlling genome organization, stability and gene expression, and by gatekeeping the activation of cell death pathways in disease. In this regard, recent studies in Drosophila, validated in mammals, have uncovered mechanism of regulation of LaminB structure and function in response to mechanical and proteotoxic stress, conditions that characterize brain neuron aging and death in different neurodegenerative pathologies, including tauopathies, such as Alzheimer’s (AD) (Napoletano et al., 2021; ), polyglutamine diseases, such as Dentatorubral-pallidoluysian atrophy (DRPLA) (Nisoli et al., 2010; Napoletano et al., 2011; Napoletano et al., 2019; ; ), C9ORF72-associated Amyotrophic Lateral Sclerosis/Fronto-Temporal Dementia (ALS/FTD) (), and autolysosomal disorders, such as Vici Syndrome (; ; Napoletano et al., 2019).
Control of cell homeostasis in response to stress requires spatiotemporal regulation of signaling, which involves protein PTMs, and among these mainly phosphorylation. Many key protein kinases controlling cell homeostasis, survival and proliferation (e.g., CDKs and MAPKs) target Serine and Threonine residues preceding a Proline (Pro-directed kinases) (Lu and Zhou, 2024). A unique feature of Pro residues is that they can acquire cis and trans structures, determining different protein stereoisomers that often have different functions. The isomerization of these S/T-P sites specifically upon phosphorylation acts a conformational checkpoint for key proteins, thus fine-tuning signaling (Zannini et al., 2019). This reaction is catalyzed by a unique enzyme conserved from yeast to humans, the phosphorylation-dependent peptidyl-prolyl isomerase Pin1, which thus functions as a crucial modulator of several cellular processes, including cell growth, death, stress response, and is implicated in multiple diseases (Lee et al., 2022). Pin1 is overexpressed in several cancers, contributing to tumor progression and metastasis, and it is an actionable target in anti-cancer approaches (Rustighi et al., 2009; Rustighi et al., 2014; Girardini et al., 2011; ). Conversely, Pin1 is reduced/inactivated during aging and in neurodegenerative pathologies such as AD, contributing to pathogenesis (Napoletano et al., 2021). Also, loss of Pin1 function in Drosophila Pin1/Dodo mutant flies and Pin1 knockout mice causes premature aging phenotypes, including degeneration of brain neurons, retina and gonads (Liou et al., 2003; Napoletano et al., 2021).
Phosphorylation plays a key role in the regulation of Lamins and several other proteins implicated in the transduction of mechanical cues impacting on chromatin through cytoskeleton-LINC connection. Interestingly, Drosophila models pioneered the discovery of a pathway crucial for genome stability in brain neurons in response to mechanical stress, through Pin1-dependent maintenance of LaminB structure and tethering of Heterochromatin protein-1alpha (HP1alpha), the major promoter of heterochromatin condensation (Napoletano et al., 2021). In conditions of reduced Pin1 levels/activity and mechanical stress, such as aging and AD (Napoletano et al., 2021; Schmid et al., 2024), LaminB deforms and HP1a is degraded via the Drosophila Hecw/mammalian NEDL/HECW-1/2 Ubiquitin ligase (; Napoletano et al., 2021). This unleashes heterochromatin derepression and mobilization of transposable elements (TEs), which cause insertional damage to DNA, leading to cell death and activation of pro-inflammatory pathways (Napoletano et al., 2021).
Furthermore, Drosophila models were instrumental to uncover the role of LaminB regulation in the death of neurons in conditions of proteotoxic stress caused by chronic autophagy impairment, including polyglutamine diseases, such as DRPLA, AD, and C9ORF72-associated ALS/FTD (; ; ). These conditions were shown to lead to the activation of a regulated cell death non-apoptotic pathway involving p38-mediated site-specific LaminB phosphorylation and consequent breakdown with cellular expulsion of nuclear material, thus dubbed karyoptosis.
Together, this evidence highlights the key role of LaminB post-translational regulation in steering neuronal stress response towards homeostasis during aging or cell demise in disease, underscoring the power of Drosophila to understand the underlying fundamental mechanisms (Figure 1).
Discussion
The evidence reviewed above highlights the fundamental role of the regulation of NE and LaminB structure and function as a determinant of neuronal health and disease. Regulation of LaminB abundance, conformation and assembly by PTMs emerges as a stress-integration gatekeeper controlling neuronal response to macro/micro-environmental biophysical and biochemical cues, which maintains neuronal homeostasis and whose impairment drives neuronal aging and non-apoptotic death in neurodegenerative diseases (Figure 1). Upon stressful stimuli typical of brain neuron aging and death in neurodegenerative diseases, such as mechanical stress, neurons mount an adaptive response involving maintenance of LaminB structure and thus tethering of heterochromatin, dependent on Pin1. With age, reduction of Pin1 levels/activity impairs this response, driving TE derepression and mobilization, with consequent DNA damage-dependent cell death. Also, LaminB is sensitive to chronic proteotoxic stress by autophagy impairment, which leads to its dismantling through karyoptosis. Causal chain from LaminB phosphorylation to karyoptosis has not been yet dissected in mammalian neurons in vivo, and it may open opportunities to inhibit neuronal death and thus provide a window for intervention in ALS/FTD and antolysosomal diseases.
Therapeutically, these findings suggest that LaminB pathways may be targeted at different levels including preservation of Pin1-dependent LaminB-heterochromatin axis, promoting nuclear-envelope repair, inhibiting retrotransposon activity (e.g., by reverse transcriptase inhibitors), limiting pathological LaminB phosphorylation (e.g., by p38 MAPK) and dismantling during proteotoxic or mitochondrial stress, enhancing autophagy–lysosomal function.
Notably, accumulating evidence suggest that the regulation of NE and Lamin structure and function in response to macro/micro-environmental biophysical and biochemical cues is fundamental to maintain the homeostasis also of non-neuronal cells. For instance, it has been recently shown that, in cancer cells, tethering of CREB3 to the Lamin nucleoskeleton maintains NE mechanical integrity. Under endoplasmic-reticulum stress, CREB3 is abnormally cleaved and drives karyoptosis (Lee et al., 2024; Jeung et al., 2025).
Regarding the regulation of Lamin proteins, their structure and function is heavily modulated by PTMs (Murray-Nerger and Cristea, 2021). Among these, phosphorylation plays a key role (Machowska et al., 2015; Torvaldson et al., 2015; Liu and Ikegami, 2020; Zheng et al., 2022; ). Lamins contain several phosphosites, of which the best characterized are those subject to hyperphosphorylation by Cyclin-dependent protein kinases (CDKs) promoting NE breakdown in mitosis. Yet the regulatory role of many of phosphosites in interphase is only partially understood. The evidence discussed above (Napoletano et al., 2021; ) suggest that, in neurons, the pattern and level of phosphorylation play a key role in the maintenance of LaminB in brain neurons and the execution of karyoptosis in conditions of altered proteostasis. In addition, farnesylation plays an important role, for instance being required for LaminB1 function in neuronal chromatin organization and migration during development in mice (Jung et al., 2013).
Key mechanisms controlling neuronal health are still incompletely understood, and important caveats remain. B-type Lamins are dispensable in some contexts, for instance for the survival and growth of mouse embryonic stem cells (Kim et al., 2011; 2013). Also, mice can develop without B-type Lamins, though with important defects in neuronal cell shape, division, nuclear integrity and migration, and cortical/cerebellar layering, with a lissencephaly-like phenotype (Vergnes et al., 2004; ; ). In addition, germline LaminB1 duplication and other genomic rearrangements cause autosomal dominant leukodystrophy, an adult-onset demyelinating disease which has been shown to be driven by the dysfunction of oligodendrocytes (Padiath et al., 2006; Heng et al., 2013; Giorgio et al., 2014; Mezaki et al., 2018; Nmezi et al., 2019; Koufi et al., 2023).
As showcased by LaminB-dependent pathways, Drosophila stands as a paramount model to keep advancing the knowledge of the fundamental mechanisms by which neuronal compartmentalization, homeostasis, and stress response are controlled in response to micro/macro-environmental cues, and their impairment drives cell dysfunction and death in disease.
Statements
Author contributions
FN: Conceptualization, Funding acquisition, Writing – original draft, Writing – review and editing, Supervision.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgments
I apologize to colleagues whose work could not be cited owing to space constraints.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
BaronO.FantoM. (2018). Karyoptosis: a novel type of cell death caused by chronic autophagy inhibition. Autophagy14, 722–723. 10.1080/15548627.2018.1434372
2
BaronO.BoudiA.DiasC.SchillingM.NölleA.Vizcay-BarrenaG.et al (2017). Stall in canonical autophagy-lysosome pathways prompts nucleophagy-based nuclear breakdown in neurodegeneration. Curr. Biol.27, 3626–3642.e6. 10.1016/j.cub.2017.10.054
3
BartonL. J.SoshnevA. A.GeyerP. K. (2015). Networking in the nucleus: a spotlight on LEM-Domain proteins. Curr. Opin. Cell Biol.34, 1–8. 10.1016/j.ceb.2015.03.005
4
BertolioR.NapoletanoF.ManoM.Maurer-StrohS.FantuzM.ZanniniA.et al (2019). Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism. Nat. Commun.10, 1326. 10.1038/s41467-019-09152-7
5
bin ImtiazM. K.JaegerB. N.BottesS.MachadoR. A. C.VidmarM.MooreD. L.et al (2021). Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity. Cell Stem Cell28, 967–977.e8. 10.1016/J.STEM.2021.01.015
6
BorahS.DhanasekaranK.KumarS. (2022). The LEM-ESCRT toolkit: repair and maintenance of the nucleus. Front. Cell Dev. Biol.10, 989217. 10.3389/FCELL.2022.989217/PDF
7
BuchwalterA.KaneshiroJ. M.HetzerM. W. (2019). Coaching from the sidelines: the nuclear periphery in genome regulation. Nat. Rev. Genet.20, 39–50. 10.1038/s41576-018-0063-5
8
CampanerE.RustighiA.ZanniniA.CristianiA.PiazzaS.CianiY.et al (2017). A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. Nat. Commun.8, 15772. 10.1038/ncomms15772
9
CastertonR.Martinez-CotrinaA.BarnardJ.WycherleyE.HuY.AndersonR.et al (2026). Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress. Nat. Commun.17, 5135. 10.1038/S41467-026-73802-W
10
CharliA.ChangY. T.LuoJ.PalanisamyB.MalovicE.RiazZ.et al (2025). Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases. Front. Cell. Neurosci.19, 1549265. 10.3389/FNCEL.2025.1549265/ABSTRACT
11
ChenH.ZhengX.ZhengY. (2014). Age-associated loss of lamin-B leads to systemic inflammation and gut hyperplasia. Cell159, 829–843. 10.1016/J.CELL.2014.10.028
12
ChengX. T.HuangN.ShengZ. H. (2022). Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration. Neuron110, 1899–1923. 10.1016/J.NEURON.2022.03.015
13
ChioloI.AltmeyerM.LegubeG.MekhailK. (2025). Nuclear and genome dynamics underlying DNA double-strand break repair. Nat. Rev. Mol. Cell Biol.26, 538–557. 10.1038/S41580-025-00828-1
14
CoffinierC.ChangS. Y.NobumoriC.TuY.FarberE. A.TothJ. I.et al (2010). Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency. Proc. Natl. Acad. Sci. U. S. A.107, 5076–5081. 10.1073/PNAS.0908790107
15
CoffinierC.JungH. J.NobumoriC.ChangS.TuY.BarnesR. H.et al (2011). Deficiencies in lamin B1 and lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons. Mol. Biol. Cell22, 4683–4693. 10.1091/mbc.E11-06-0504
16
CongB.CaganR. L. (2024). Cell competition and cancer from drosophila to mammals. Oncogenesis13, 1. 10.1038/S41389-023-00505-Y
17
CorballyM. K.ReganJ. C. (2022). Fly immunity comes of age: the utility of drosophila as a model for studying variation in immunosenescence. Front. Aging3, 1016962. 10.3389/FRAGI.2022.1016962
18
CornelisonG. L.LevyS. A.JensonT.FrostB. (2019). Tau-induced nuclear envelope invagination causes a toxic accumulation of mRNA in drosophila. Aging Cell18, e12847. 10.1111/acel.12847
19
Costa-MattioliM.WalterP. (2020). The integrated stress response: from mechanism to disease. Science368, eaat5314. 10.1126/SCIENCE.AAT5314
20
CoyneA. N.RothsteinJ. D. (2022). Nuclear pore complexes — a doorway to neural injury in neurodegeneration. Nat. Rev. Neurol.18, 348–362. 10.1038/S41582-022-00653-6
21
CristofoliF.MossT.MooreH. W.DevriendtK.Flanagan-SteetH.MayM.et al (2020). De novo Variants in LMNB1 Cause Pronounced Syndromic Microcephaly and Disruption of Nuclear Envelope Integrity. Am. J. Hum. Genet.107, 753–762. 10.1016/J.AJHG.2020.08.015/ATTACHMENT/028F7C9C-64B8-4EF8-9B18-D978BDEE88A0/MMC2
22
Dalla CostaI.BuchananC. N.ZdradzinskiM. D.SahooP. K.SmithT. P.ThamesE.et al (2021). The functional organization of axonal mRNA transport and translation. Nat. Rev. Neurosci.22, 77–91. 10.1038/S41583-020-00407-7
23
De Sandre-GiovannoliA.ChaouchM.KozlovS.VallatJ. M.TazirM.KassouriN.et al (2002). Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (charcot-marie-tooth disorder type 2) and mouse. Am. J. Hum. Genet.70, 726–736. 10.1086/339274
24
Delint-RamirezI.MadabhushiR. (2025). DNA damage and its links to neuronal aging and degeneration. Neuron113, 7–28. 10.1016/J.NEURON.2024.12.001
25
Della ValleF.ReddyP.Aguirre VazquezA.Izpisua BelmonteJ. C. (2025). Reactivation of retrotransposable elements is associated with environmental stress and ageing. Nat. Rev. Genet.26, 547–558. 10.1038/S41576-025-00829-Y
26
DenaisC. M.GilbertR. M.IsermannP.McGregorA. L.Te LindertM.WeigelinB.et al (2016). Nuclear envelope rupture and repair during cancer cell migration. Science.352, 353–358. 10.1126/science.aad7297
27
DialynasG.FlanneryK. M.ZirbelL. N.NagyP. L.MathewsK. D.MooreS. A.et al (2012). LMNA variants cause cytoplasmic distribution of nuclear pore proteins in drosophila and human muscle. Hum. Mol. Genet.21, 1544–1556. 10.1093/HMG/DDR592
28
Dichtel-DanjoyM. L.MaD.DourlenP.ChatelainG.NapoletanoF.RobinM.et al (2013). Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation. Cell Death Differ.20, 108–116. 10.1038/cdd.2012.100
29
DourlenP.BertinB.ChatelainG.RobinM.NapoletanoF.RouxM. J.et al (2012). Drosophila fatty acid transport protein regulates rhodopsin-1 metabolism and is required for photoreceptor neuron survival. PLoS Genet.8, e1002833. 10.1371/journal.pgen.1002833
30
FajnerV.GiavazziF.SalaS.OldaniA.MartiniE.NapoletanoF.et al (2021). Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles. Nat. Commun.12, 5488. 10.1038/S41467-021-25809-8
31
FanJ.XuY. (2026). Molecular mechanisms underlying the lifespan and healthspan benefits of dietary restriction across species. Front. Genet.17, 1771707. 10.3389/FGENE.2026.1771707
32
FeiY.DingY. (2024). The role of ferroptosis in neurodegenerative diseases. Front. Cell. Neurosci.18, 1475934. 10.3389/FNCEL.2024.1475934/FULL
33
FernandopulleM. S.Lippincott-SchwartzJ.WardM. E. (2021). RNA transport and local translation in neurodevelopmental and neurodegenerative disease. Nat. Neurosci.24, 622–632. 10.1038/S41593-020-00785-2
34
FouilletA.LevetC.VirgoneA.RobinM.DourlenP.RieussetJ.et al (2012). ER stress inhibits neuronal death by promoting autophagy. Autophagy8, 915–926. 10.4161/AUTO.19716
35
FrostB.BardaiF. H.FeanyM. B. (2016). Lamin dysfunction mediates neurodegeneration in tauopathies. Curr. Biol.26, 129–136. 10.1016/j.cub.2015.11.039
36
GiandomenicoS. L.Alvarez-CastelaoB.SchumanE. M. (2022). Proteostatic regulation in neuronal compartments. Trends Neurosci.45, 41–52. 10.1016/j.tins.2021.08.002
37
GiorgioE.RobyrD.SpielmannM.FerreroE.Di GregorioE.ImperialeD.et al (2014). A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD). Hum. Mol. Genet.24, 3143–3154. 10.1093/hmg/ddv065
38
GirardiniJ. E.NapoliM.PiazzaS.RustighiA.MarottaC.RadaelliE.et al (2011). A Pin1/Mutant p53 axis promotes aggressiveness in breast cancer. Cancer Cell20, 79–91. 10.1016/j.ccr.2011.06.004
39
HalfmannC. T.SearsR. M.KatiyarA.BusselmanB. W.AmanL. K.ZhangQ.et al (2019). Repair of nuclear ruptures requires barrier-to-autointegration factor. J. Cell Biol.218, 2136–2149. 10.1083/JCB.201901116
40
HengM. Y.LinS. T.VerretL.HuangY.KamiyaS.PadiathQ. S.et al (2013). Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model. J. Clin. Investigation123, 2719–2729. 10.1172/JCI66737
41
HetzC.ZhangK.KaufmanR. J. (2020). Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol.21, 421–438. 10.1038/s41580-020-0250-z
42
HoJ. S. Y.DouseC. H.MarazziI. (2026). Transposable element DNA and RNA: drivers of gene expression, evolution, and disease. Cell189, 3513–3540. 10.1016/J.CELL.2026.05.003
43
Ho-TiengD.SharmaV.SonenbergN.GkogkasC. G.KhoutorskyA. (2025). The integrated stress response in the brain: cell type-specific functions in health and neurological disorders. Trends Neurosci.48, 808–821. 10.1016/J.TINS.2025.08.002
44
JeungD.LiX.ChoY. Y. (2025). New roles of bZIP-Containing membrane-bound transcription factors in chromatin tethering and karyoptosis. Int. J. Mol. Sci.26, 10896. 10.3390/IJMS262210896
45
Jimenez-BlascoD.LapresaR.AgullaJ.AlmeidaA.BolañosJ. P. (2026). Neuronal glycolysis meets mitophagy to govern organismal wellbeing. Trends Endocrinol. Metabolism37, 8–16. 10.1016/j.tem.2025.05.005
46
JungH. J.CoffinierC.ChoeY.BeigneuxA. P.DaviesB. S. J.YangS. H.et al (2012). Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA. Proc. Natl. Acad. Sci. U. S. A.109, E423. 10.1073/PNAS.1111780109/-/DCSUPPLEMENTAL
47
JungH. J.NobumoriC.GoulbourneC. N.TuY.LeeJ. M.TatarA.et al (2013). Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration. Proc. Natl. Acad. Sci. U. S. A.110, E1923–E1932. 10.1073/PNAS.1303916110
48
KalukulaY.StephensA. D.LammerdingJ.GabrieleS. (2022). Mechanics and functional consequences of nuclear deformations. Nat. Rev. Mol. Cell Biol.23, 583–602. 10.1038/s41580-022-00480-z
49
KampmannM. (2024). Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases. Nat. Rev. Neurosci.25, 351–371. 10.1038/S41583-024-00806-0
50
KaroutasA.AkhtarA. (2021). Functional mechanisms and abnormalities of the nuclear lamina. Nat. Cell Biol.23, 116–126. 10.1038/S41556-020-00630-5
51
KhanC.RusanN. M. (2024). Using drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer. Trends Cancer10, 289–311. 10.1016/J.TRECAN.2024.01.007
52
KhorS.CaiD. (2020). Control of lifespan and survival by drosophila NF-KB signaling through neuroendocrine cells and neuroblasts. Aging12, 24604–24622. 10.18632/AGING.104196
53
KimY.SharovA. A.McDoleK.ChengM.HaoH.FanC. M.et al (2011). Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells. Science.334, 1706–1710. 10.1126/SCIENCE.1211222
54
KimY.ZhengX.ZhengY. (2013). Proliferation and differentiation of mouse embryonic stem cells lacking all lamins. Cell Res.23, 1420–1423. 10.1038/CR.2013.118
55
KimS.CoukosR.GaoF.KraincD. (2022). Dysregulation of organelle membrane contact sites in neurological diseases. Neuron110, 2386–2408. 10.1016/j.neuron.2022.04.020
56
KirbyT. J.LammerdingJ. (2018). Emerging views of the nucleus as a cellular mechanosensor. Nat. Cell Biol.20, 373–381. 10.1038/s41556-018-0038-y
57
KonopkaA.AtkinJ. D. (2022). The role of DNA damage in neural plasticity in physiology and neurodegeneration. Front. Cell. Neurosci.16, 836885. 10.3389/FNCEL.2022.836885/FULL
58
KoufiF. D.NeriI.RamazzottiG.RuscianoI.MongiorgiS.MarviM. V.et al (2023). Lamin B1 as a key modulator of the developing and aging brain. Front. Cell. Neurosci.17, 1263310. 10.3389/FNCEL.2023.1263310/FULL
59
LeeJ. M.TuY.TatarA.WuD.NobumoriC.JungH. J.et al (2014). Reciprocal knock-in mice to investigate the functional redundancy of lamin B1 and lamin B2. Mol. Biol. Cell25, 1676–1685. 10.1091/MBC.E14-01-0683
60
LeeY. M.TeohD. E. J.YeungK.LiouY. C. (2022). The kingdom of the prolyl-isomerase Pin1: the structural and functional convergence and divergence of Pin1. Front. Cell Dev. Biol.10, 956071. 10.3389/FCELL.2022.956071/FULL
61
LeeG. E.BangG.ByunJ.LeeC. J.ChenW.JeungD.et al (2024). Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death. Exp. Mol. Med.56, 686–699. 10.1038/S12276-024-01195-1
62
LeiP.WalkerT.AytonS. (2025). Neuroferroptosis in health and diseases. Nat. Rev. Neurosci.26, 497–511. 10.1038/S41583-025-00930-5
63
Lenz-BöhmeB.WismarJ.FuchsS.ReifegersteR.BuchnerE.BetzH.et al (1997). Insertional mutation of the drosophila nuclear lamin Dm0 gene results in defective nuclear envelopes, clustering of nuclear pore complexes, and accumulation of annulate lamellae. J. Cell Biol.137, 1001–1016. 10.1083/JCB.137.5.1001
64
LiY.HassingerL.ThomsonT.DingB.AshleyJ.HassingerW.et al (2016). Lamin mutations accelerate aging via defective export of mitochondrial mRNAs through nuclear envelope budding. Curr. Biol.26, 2052–2059. 10.1016/j.cub.2016.06.007
65
LiouY. C.SunA.RyoA.ZhouX. Z.YuZ. X.HuangH. K.et al (2003). Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature424, 556–561. 10.1038/nature01832
66
LiuJ.HetzerM. W. (2022). Nuclear pore complex maintenance and implications for age-related diseases. Trends Cell Biol.32, 216–227. 10.1016/J.TCB.2021.10.001
67
LiuS. Y.IkegamiK. (2020). Nuclear lamin phosphorylation: an emerging role in gene regulation and pathogenesis of laminopathies. Nucleus11, 299–314. 10.1080/19491034.2020.1832734
68
López-OtínC.KroemerG. (2021). Hallmarks of health. Cell184, 33–63. 10.1016/J.CELL.2020.11.034
69
LuK. P.ZhouX. Z. (2024). Pin1-catalyzed conformational regulation after phosphorylation: a distinct checkpoint in cell signaling and drug discovery. Sci. Signal.17, 1–27. 10.1126/scisignal.adi8743
70
LvT.WangC.ZhouJ.FengX.ZhangL.FanZ. (2024). Mechanism and role of nuclear laminin B1 in cell senescence and malignant tumors. Cell Death Discov. 202410 (1), 269. 10.1038/s41420-024-02045-9
71
MachowskaM.PiekarowiczK.RzepeckiR. (2015). Regulation of lamin properties and functions: does phosphorylation do it all?Open Biol.5, 150094. 10.1098/rsob.150094
72
MattsonM. P.ArumugamT. V. (2018). Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab.27, 1176–1199. 10.1016/J.CMET.2018.05.011
73
MengistuD. Y.MarzulloM.PellacaniC.MarchettiM.TerribiliM.Montivero MoralesE.et al (2026). “Microcephaly-associated genes asp and Sas4 influence chromatin organization and nuclear lamina structure in Drosophila melanogaster,”Development153, dev205125. 10.1242/DEV.205125/3697377/DEV205125.PDF
74
MezakiN.MiuraT.OgakiK.EriguchiM.MizunoY.KomatsuK.et al (2018). Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy. Neurol. Genet.4, e292. 10.1212/NXG.0000000000000292
75
MollereauB.ManiéS.NapoletanoF. (2014). Getting the better of ER stress. J. Cell Commun. Signal.8, 311–321. 10.1007/s12079-014-0251-9
76
Murray-NergerL. A.CristeaI. M. (2021). Lamin post-translational modifications: emerging toggles of nuclear organization and function. Trends biochem. Sci.46, 832–847. 10.1016/j.tibs.2021.05.007
77
NaganoS.ArakiT. (2021). Axonal transport and local translation of mRNA in neurodegenerative diseases. Front. Mol. Neurosci.14, 697973. 10.3389/FNMOL.2021.697973/PDF
78
NapoletanoF.OcchiS.CalamitaP.VolpiV.BlancE.CharrouxB.et al (2011). Polyglutamine atrophin provokes neurodegeneration in drosophila by repressing fat. EMBO J.30, 945–958. 10.1038/emboj.2011.1
79
NapoletanoF.GibertB.Yacobi-SharonK.VincentS.FavrotC.MehlenP.et al (2017). p53-dependent programmed necrosis controls germ cell homeostasis during spermatogenesis. PLoS Genet.13, e1007024. 10.1371/journal.pgen.1007024
80
NapoletanoF.BaronO.VandenabeeleP.MollereauB.FantoM. (2019). Intersections between regulated cell death and autophagy. Trends Cell Biol.29, 323–338. 10.1016/j.tcb.2018.12.007
81
NapoletanoF.Ferrari BravoG.VotoI. A. P.SantinA.CeloraL.CampanerE.et al (2021). The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress. Cell Rep.36, 109694. 10.1016/j.celrep.2021.109694
82
NisoliI.ChauvinJ. P.NapoletanoF.CalamitaP.ZaninV.FantoM.et al (2010). Neurodegeneration by polyglutamine atrophin is not rescued by induction of autophagy. Cell Death Differ.17, 1577–1587. 10.1038/cdd.2010.31
83
NixonR. A.RubinszteinD. C. (2024). Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases. Nat. Rev. Mol. Cell Biol.25, 926–946. 10.1038/S41580-024-00757-5
84
NmeziB.GiorgioE.RaininkoR.LehmanA.SpielmannM.KoenigM. K.et al (2019). Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy. Neurol. Genet.5, e305. 10.1212/NXG.0000000000000305
85
OdellJ.LammerdingJ. (2023). Lamins as structural nuclear elements through evolution. Curr. Opin. Cell Biol.85, 102267. 10.1016/j.ceb.2023.102267
86
OhH. S. H.Le GuenY.RappoportN.UreyD. Y.FarinasA.RutledgeJ.et al (2025). Plasma proteomics links brain and immune system aging with healthspan and longevity. Nat. Med.31 (8), 2703–2711. 10.1038/s41591-025-03798-1
87
OsoudaS.NakamuraY.De Saint PhalleB.McConnellM.HorigomeT.SugiyamaS.et al (2005). Null mutants of drosophila B-type lamin Dm0 show aberrant tissue differentiation rather than obvious nuclear shape distortion or specific defects during cell proliferation. Dev. Biol.284, 219–232. 10.1016/j.ydbio.2005.05.022
88
OystonL. J.LinY. Q.KhuongT. M.WangQ.-P.LauM. T.ClarkT.et al (2018). Neuronal lamin regulates motor circuit integrity and controls motor function and lifespan. Cell Stress2, 225–232. 10.15698/cst2018.09.152
89
PadiathQ. S.SaigohK.SchiffmannR.AsaharaH.YamadaT.KoeppenA.et al (2006). Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat. Genet.38 (10), 1114–1123. 10.1038/ng1872
90
ParryD. A.MartinC. A.GreeneP.MarshJ. A.AmbroseJ. C.ArumugamP.et al (2021). Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy. Genet. Med.23, 408–414. 10.1038/S41436-020-00980-3
91
PatkeA.YoungM. W.AxelrodS. (2020). Molecular mechanisms and physiological importance of circadian rhythms. Nat. Rev. Mol. Cell Biol.21, 67–84. 10.1038/S41580-019-0179-2
92
RaabM.GentiliM.De BellyH.ThiamH. R.VargasP.JimenezA. J.et al (2016). ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science.352, 359–362. 10.1126/science.aad7611
93
RadulovicM.YangC.StenmarkH. (2026). Lysosomal membrane homeostasis and its importance in physiology and disease. Nat. Rev. Mol. Cell Biol.27, 71–87. 10.1038/S41580-025-00873-W
94
RobinM.IssaA. R.SantosC. C.NapoletanoF.PetitgasC.ChatelainG.et al (2019). Drosophila p53 integrates the antagonism between autophagy and apoptosis in response to stress. Autophagy15, 771–784. 10.1080/15548627.2018.1558001
95
RustighiA.TiberiL.SoldanoA.NapoliM.NuciforoP.RosatoA.et al (2009). The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nat. Cell Biol.11, 133–142. 10.1038/ncb1822
96
RustighiA.ZanniniA.TiberiL.SommaggioR.PiazzaS.SorrentinoG.et al (2014). Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Mol. Med.6, 99–119. 10.1002/emmm.201302909
97
SatohA.BraceC. S.RensingN.CliftenP.WozniakD. F.HerzogE. D.et al (2013). Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab.18, 416–430. 10.1016/J.CMET.2013.07.013
98
SbrizM.ShamshiddinovaM.LossiL.MerighiA. (2025). Expression of two histone H4 epigenetic modifications (lysine 12 acetylation and lysine 20 trimethylation), and the senescence marker lamin B1 in the postnatal, adult, and old mouse brain. Front. Cell Death4, 1632653. 10.3389/FCELD.2025.1632653
99
SchmidE. T.PyoJ. H.WalkerD. W. (2022). Neuronal induction of BNIP3-mediated mitophagy slows systemic aging in drosophila. Nat. Aging2, 494–507. 10.1038/S43587-022-00214-Y
100
SchmidE. T.SchinamanJ. M.Liu-AbramowiczN.WilliamsK. S.WalkerD. W. (2024). Accumulation of F-actin drives brain aging and limits healthspan in drosophila. Nat. Commun.15 (1), 9238. 10.1038/s41467-024-53389-w
101
Sladitschek-MartensH. L.GuarnieriA.BrumanaG.ZanconatoF.BattilanaG.XiccatoR. L.et al (2022). YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS–STING. Nature607, 790–798. 10.1038/s41586-022-04924-6
102
SmithT. K. T.TownsendL. K.SmilesW. J.OakhillJ. S.FullertonM. D.SteinbergG. R. (2026). AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis. Nat. Metab.8, 27–51. 10.1038/S42255-025-01442-3
103
SosaB. A.RothballerA.KutayU.SchwartzT. U. (2012). LINC complexes form by binding of three KASH peptides to domain interfaces of trimeric SUN proteins. Cell149, 1035–1047. 10.1016/j.cell.2012.03.046
104
StellerH. (2026). Thirty years of reaper: lessons learned from programmed cell death in drosophila. Front. Cell Death5, 1770008. 10.3389/FCELD.2026.1770008
105
StiekemaM.HoubenF.VerheyenF.BorgersM.MenzelJ.MeschkatM.et al (2022). The role of lamins in the nucleoplasmic reticulum, a pleiomorphic organelle that enhances nucleo-cytoplasmic interplay. Front. Cell Dev. Biol.10, 914286. 10.3389/FCELL.2022.914286/FULL
106
TokizaneK.ImaiS. ichiro (2025). Inter-organ communication is a critical machinery to regulate metabolism and aging. Trends Endocrinol. and Metabolism36, 756–766. 10.1016/J.TEM.2024.11.013
107
TokizaneK.BraceC. S.ImaiS. ichiro (2024). DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication. Cell Metab.36, 377–392.e11. 10.1016/J.CMET.2023.12.011
108
TorvaldsonE.KochinV.ErikssonJ. E. (2015). Phosphorylation of lamins determine their structural properties and signaling functions. Nucleus6, 166–171. 10.1080/19491034.2015.1017167
109
TsengC. S.ChaoY. W.LiuY. H.HuangY. S.ChaoH. W. (2023). Dysregulated proteostasis network in neuronal diseases. Front. Cell Dev. Biol.11, 1075215. 10.3389/FCELL.2023.1075215/PDF
110
UlianovS. V.DoroninS. A.KhrameevaE. E.KosP. I.LuzhinA. V.StarikovS. S.et al (2019). Nuclear lamina integrity is required for proper spatial organization of chromatin in drosophila. Nat. Commun.10, 1176. 10.1038/S41467-019-09185-Y
111
VergnesL.TerfyP.BergoM. O.YoungS. G.ReueK. (2004). Lamin B1 is required for mouse development and nuclear integrity. Available online at: www.pnas.orgcgidoi10.1073pnas.0401424101 (Accessed August 5, 2026).
112
VerheyenE. M. (2022). The power of drosophila in modeling human disease mechanisms. Dis. Model. Mech.15, dmm049549. 10.1242/DMM.049549
113
WongX.Melendez-PerezA. J.ReddyK. L. (2022). The nuclear lamina. Cold Spring Harb. Perspect. Biol.14, a040113. 10.1101/cshperspect.a040113
114
WuT.XuH.ChengL.WuR.GuoF.ChenX. (2025). The nuclear envelope and nuclear pore complexes in neurodegenerative diseases. Front. Cell Dev. Biol.13, 1550859. 10.3389/FCELL.2025.1550859/ABSTRACT
115
Yacobi-SharonK.NamdarY.AramaE. (2013). Alternative germ cell death pathway in drosophila involves HtrA2/Omi, lysosomes, and a caspase-9 counterpart. Dev. Cell25, 29–42. 10.1016/J.DEVCEL.2013.02.002
116
YücelA. D.GladyshevV. N. (2026). Systemic epigenetic dysregulation as a driver of ageing and a therapeutic target. Nat. Rev. Mol. Cell Biol.27, 528–542. 10.1038/S41580-026-00958-0
117
ZanniniA.RustighiA.CampanerE.Del SalG. (2019). Oncogenic hijacking of the PIN1 signaling network. Front. Oncol.9, 94. 10.3389/fonc.2019.00094
118
ZhangG.LiJ.PurkayasthaS.TangY.ZhangH.YinY.et al (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature497, 211–216. 10.1038/NATURE12143
119
ZhengM.JinG.ZhouZ. (2022). Post-translational modification of lamins: mechanisms and functions. Front. Cell Dev. Biol.10, 864191. 10.3389/FCELL.2022.864191/FULL
120
ZhuH.CohenE. (2023). Regulation of the proteostasis network by the neuronal system. Front. Mol. Biosci.10, 1290118. 10.3389/FMOLB.2023.1290118/FULL
121
ZulloJ. M.DrakeD.AronL.O’HernP.DhamneS. C.DavidsohnN.et al (2019). Regulation of lifespan by neural excitation and REST. Nat. 2019574 (7), 359–364. 10.1038/s41586-019-1647-8
Summary
Keywords
epigenetics and heterochromatin in genome instability, lamin in aging and cell death, mechanical stress in neurodegenerative diseases, nuclear envelope integrity, rupture and repair, phosphorylation-dependent prolyl-isomerase Pin1, proteostasis and autophagy in karyoptosis, signaling in brain health, transposons in inflammation and senescence
Citation
Napoletano F (2026) At the nucleus of neuronal health: Drosophila insights into LaminB-dependent homeostasis in aging and cell death. Front. Cell Death 5:1954383. doi: 10.3389/fceld.2026.1954383
Received
31 July 2026
Revised
07 August 2026
Accepted
17 August 2026
Published
04 September 2026
Volume
5 - 2026
Edited by
Bertrand Mollereau, Université de Lyon, France
Reviewed by
Manolis Fanto, King’s College London, United Kingdom
Updates
Copyright
© 2026 Napoletano.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Francesco Napoletano, fnapoletano@units.it
ORCID: Francesco Napoletano, orcid.org/0000-0002-0910-3167
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.