Alpha-Synuclein dynamics in Cellular and Molecular Mechanisms of Brain-aging

Alpha-Synuclein is a presynaptic neuronal protein essential for vesicle trafficking and neurotransmitter release. While widely recognized for its pathological aggregation in disorders such as Parkinson’s disease and Dementia with Lewy Bodies, its dynamics during the natural course of brain aging remain complex. Aging is characterized by a gradual loss of proteostatic control, synaptic efficacy, and altered cellular signaling. In this context, alpha-synuclein undergoes significant changes in expression, post-translational modification, and clearance even in the absence of overt disease. Understanding the nuanced shift from physiological function to pathological dysfunction is critical. As the global population ages, distinguishing between benign age-related changes in alpha-synuclein dynamics and those driving neurodegeneration is essential for developing early interventions and maintaining cognitive health.

The primary goal of this Research Topic is to broaden the understanding of alpha-synuclein beyond its role as a static disease marker, focusing instead on its dynamic behavior within the aging cellular environment. We aim to explore the mechanistic "tipping points" where normal age-dependent alterations in alpha-synuclein homeostasis transition into toxic cascades.

Despite progress in in vivo imaging and the development of Seeding Amplification Assays (SAAs), the temporal relationship between molecular changes—such as oligomerization, phase separation, and spreading—and the functional decline of the aging brain remains elusive. This topic seeks to integrate advances in biochemistry, genetics, and systems biology to uncover how the aging microenvironment (including oxidative stress and inflammation) influences alpha-synuclein. By fostering a deeper understanding of these upstream molecular events, we aim to identify novel therapeutic targets that can preserve neuronal function or enhance clearance mechanisms before irreversible aggregation occurs.

We seek to define the scope of this topic broadly, welcoming contributions that investigate alpha-synuclein through the lens of cellular aging and molecular biology. We encourage submissions addressing, but not limited to, the following themes:

• Mechanisms of alpha-synuclein clearance (autophagy, lysosomal, proteasomal) and their efficiency in the aging brain.

• The impact of alpha-synuclein dynamics on synaptic plasticity, vesicle recycling, and neuronal connectivity.

• Interplay between alpha-synuclein, mitochondrial dysfunction, and lipid metabolism.

• The role of non-neuronal cells (microglia, astrocytes) and neuroinflammation in regulating alpha-synuclein burden.

• Genetic and epigenetic modulators of alpha-synuclein expression during senescence.

• Novel methodologies (SAAs, advanced imaging) for tracking dynamic changes in aging cohorts.



We welcome Original Research, Reviews, Mini-Reviews, and Perspective articles.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: alpha-synuclein; brain aging; proteostasis; synaptic plasticity; neurodegeneration

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.