Editorial: Cell death mechanisms in neurodegenerative disorders

Editorial on the Research Topic
Cell death mechanisms in neurodegenerative disorders

Introduction

Cell death regulation is one of the important features that underlies the health and diseased conditions. All major neurodegenerative and neurological disorders inclusive of cancers and neurodegeneration can widely be attributed to dysregulated cell death mechanisms. Millions of people worldwide suffer from neurological and neurodegenerative disorders such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amylotrophic Lateral Sclerosis (ALS), Huntington’s Disease (HD), Multiple Sclerosis (MS) and Stroke (Sarkar et al., 2016; Narwal et al., 2024). A common underlying feature for all these conditions is neuronal cell death, which has been studied in great detail by researchers for understanding the “cause and the effect” of the symptoms (Singh, 2012). Current understanding gathered from different model organisms, organoid transplants and the in-vitro approaches points in the direction that the majority of neurodegenerative disorders are due to proteinopathies, which eventually result in neuronal cell death.

This Research Topic emphasizes on the advancements in understanding the varied mechanisms underlying different types of cell death(s) during the course of neurodegenerative disorders. The Research Topic advances the understanding and raises new questions to aid ongoing research across different model systems. Conservation of genetic machinery and amenability of various models to genetic manipulation helped address these questions in various animal models. We believe that this Research Topic enables researchers to develop detailed understanding of cell death mechanisms, unravel the gaps and missing links and identify the interconnecting pathways to discern neurodegenerative disorders to develop better therapies and management strategies.

Cell death pathways in neurodegeneration

Studies from invertebrate and mammalian models suggest that neurodegenerative disorders involving protein misfolding and aggregations such as AD, PD and ALS, are characterized by activation of various kinds of cell death pathways including apoptosis, autophagy, ferroptosis and necrosis (Rai and Bergmann, Li et al.). Interestingly, interpreted factors, which are common neurodegeneration cascades from these models are production of ROS, mitochondrial dysfunction and disturbed immune response pathways. There are multiple studies which indicate connections between protein aggregation, ROS production leading to activation of inflammatory pathways involving different types of neuronal and non-neuronal cells (Deshpande et al., 2024).

Abnormal iron homeostasis affects protein aggregations, leading to enhanced ROS production causing ferroptosis in case of PD. Studies from glia-neuron interactions have provided evidence for the role of glial cells in maintenance of iron homeostasis regulating dopaminergic neuronal loss (Li et al.). Activation of glial cells results in activation of Nuclear Factor-Kappa-B (NF-kB) which causes upregulation of inflammatory molecules, thereby causing inflammation in neuronal tissues in conditions of neurodegeneration (Reviewed in Heneka et al., 2025). In addition to apoptosis, autophagy, ferroptosis, necrosis and pyroptosis have also been well documented in conditions of neurodegeneration and neurological conditions such as stroke (Rinald and Troy).

Genetic as well as environmental factors have been extensively studied which can cause neurodegenerative and neurological diseases (Banerjee et al., 2022; Iyer et al., 2024; Yogi et al., 2025). Altered nucleic acid metabolism has also been studied in context to neurodegenerative disorders (Chimata et al., 2024; Singh et al., 2025). Interestingly, three stranded non-canonical DNA-RNA hybrid templates have also been identified to be involved in mediating cellular damage enhancing pathogenesis of several human diseases, including neurodegeneration mediated in ALS, ataxia and spinal muscular atrophy (Liu et al.).

Different kinds of cell death regulate the progression of neurodegenerative and neurological disorders/injuries, it is noteworthy that modeling of different kinds of cell death in different model systems is crucial to develop not only therapeutics, but also early diagnosis. We acknowledge the insights into cell death regulatory pathways developed from models including invertebrate models such as flies up-to mammalian systems, organoid transplants and patient samples.

Articles presented in this section have highlighted various kinds of cell deaths which mediate neuronal loss in different conditions. It is evident that mechanisms involved in mediating neurodegenerative and neurological disorders are multifactorial; possibly due to different mechanisms which mediate neuronal injury and eventual loss.

We believe that this Research Topic will aid in advancing the understanding of the field of neurodegenerative disorders in order to develop better diagnostic and therapeutic measures in future.

Author contributions

MT: Conceptualization, Writing – original draft, Writing – review and editing. BD’O: Writing – review and editing. AS: Writing – original draft, Writing – review and editing.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. AS is supported by 1RO1EY032959-01 and RO1 supplement from NIH, and Brother Leonard A Mann Chair in Natural Sciences Endowment Fund from the University of Dayton. BD’O is supported by grants from Finanziato dall’Unione europea – Next-Generation EU, Missione 4 Componente 1, CUP I53D23001020001 to BD’O. MT is supported by 5/4-5/3/22/Neuro/2022-NCD-I from ICMR, and C2/24/295 from CDRF, BITS Pilani.

Acknowledgments

We would like to thank the team of Frontiers for the invitation to host and guest edit this Research Topic, and for their consistent support through the process. We also thank all the authors who submitted their manuscripts for this Research Topic.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Generative AI statement

The author(s) declare that no Generative AI was 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

Banerjee, R., Rai, A., Iyer, S. M., Narwal, S., and Tare, M. (2022). Animal models in the study of Alzheimer's disease and Parkinson's disease: a historical perspective. Anim. Models Exp. Med. 5, 27–37. doi:10.1002/ame2.12209

PubMed Abstract | CrossRef Full Text | Google Scholar

Chimata, A. V., Deshpande, P., and Singh, A. (2024). “Altered metabolism in neurodegenerative disorders,” in Altered metabolism: a major contributor of comorbidities in neurodegenerative diseases. Editor Dr. Namita Agrawal (Springer Nature).

Google Scholar

Deshpande, P., Chen, C.-Y., Chimata, A. V., Li, J.-C., Singh, A., Sarkar, A., et al. (2024). miR-277 targets the proapoptotic gene-hid to ameliorate Aβ42-mediated neurodegeneration in Alzheimer’s model. Cell Death Dis. 15(1):71. doi:10.1038/s41419-023-06361-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., et al. (2025). Neuroinflammation in Alzheimer disease. Nat. Rev. Immunol. 25, 321–352. doi:10.1038/s41577-024-01104-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Iyer, S. M., Verma, S., Marathe, S. A., and Tare, M. * (2024). “Emerging relationship between the gut microbiota and neurodegenerative disorders,” in Altered metabolism: a major contributor of comorbidities in neurodegenerative diseases. Editor N. Agrawal (Singapore: Springer). doi:10.1007/978-981-97-4288-2_11

CrossRef Full Text | Google Scholar

Narwal, S., Singh, A., and Tare, M. (2024). Analysis of α-syn and parkin interaction in mediating neuronal death in drosophila model of Parkinson's disease. Front. Cell Neurosci. 17, 1295805. doi:10.3389/fncel.2023.1295805

PubMed Abstract | CrossRef Full Text | Google Scholar

Sarkar, A., Irwin, M., Singh, A., Riccetti, M., and Singh, A. (2016). Alzheimer's disease: the silver tsunami of the 21(st) century. Neural Regen. Res. 11 (5), 693–697. doi:10.4103/1673-5374.182680

PubMed Abstract | CrossRef Full Text | Google Scholar

Singh, A. (2012). Neurodegeneration a means to an end. Journal of cell science and therapy (editorial). J. Cell Sci. Ther. 3, e107. doi:10.4172/2157-7013.1000e107

CrossRef Full Text | Google Scholar

Singh, A., Deshpande, P., Chimata, A. V., Sangeeth, A., Bajpai, S., Subramanian, M., et al. (2025). “Factors influencing protein misfolding and aggregate formation that trigger neuronal cell death,” in Protein misfolding and neurodegenerative diseases. Editors N. Gogia, S. Singh, and D. J. Vidyadhara (Elsevier).

Google Scholar

Yogi, S., Sangeeth, A., Chimata, A. V., and Singh, A. (2025). “Genetic and molecular basis of neurodegenerative diseases,” in New era in alzheimer research: pathogenesis, prevention, diagnosis and treatment. Editors Dr. Sandeep Kumar Singh, and Dr. Ricardo Maccioni (Elsevier Press).

CrossRef Full Text | Google Scholar