Alpha-Synuclein Dynamics in Neurodegenerative Disorders

Alpha-synuclein is a small presynaptic protein that under physiological conditions exists predominantly in a soluble, monomeric state and plays roles in vesicle trafficking and neurotransmitter release. In synucleinopathies such as Parkinson’s disease and Lewy body dementia, this protein undergoes misfolding and assembles into oligomers and amyloid fibrils, which accumulate as Lewy bodies and neurites. The dynamic equilibrium between monomeric, oligomeric and fibrillar forms is governed by factors including post-translational modifications, membrane interactions and clearance pathways. Impairment of proteasomal and lysosomal degradation, including macroautophagy and chaperone-mediated autophagy, shifts this balance towards aggregate accumulation. Misfolded species can seed further aggregation in neighbouring cells via extracellular vesicles or unconventional secretion, propagating pathology through neural networks. Understanding the structural polymorphisms of fibrils, their cellular trafficking and the mechanisms of aggregate clearance has underpinned efforts to develop biomarkers for prodromal detection and targeted therapies aimed at restoring proteostasis or degrading pathogenic assemblies.

Research from Nature Portfolio

Recent studies have resolved the atomic architecture of alpha-synuclein fibrils derived from human Lewy body dementia tissue by amplifying patient-extracted fibrils and analysing them with solid-state NMR. These investigations revealed a mixture of single- and two-protofilament assemblies with a low degree of twist and a conserved core fold, expanding our understanding of strain diversity and informing rational design of imaging agents and aggregation inhibitors.

Complementing this, cryo-electron microscopy of full-length recombinant alpha-synuclein fibrils identified two predominant polymorphs—termed “rod” and “twister”—that share a bent β-arch kernel but differ in their inter-protofilament interfaces. Comparative analyses of these structures have elucidated how familial mutations may alter fibril populations, guiding drug discovery efforts that must account for concurrent polymorphs in synucleinopathies.

Alpha-Synuclein Dynamics in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in alpha-synuclein dynamics in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Alpha-synuclein: A presynaptic neuronal protein prone to misfolding and aggregation in Parkinson’s disease and related disorders.

Protofilament: A linear chain of protein subunits that associates laterally with other protofilaments to form amyloid fibrils.

Fibril polymorph: A structurally distinct form of an amyloid fibril, characterised by variations in core fold or protofilament packing.

Extracellular vesicle (EV): Membrane-bound particles released by cells that can transfer proteins and nucleic acids between cells.

AUTOTAC: A bifunctional molecule that couples a target protein or aggregate to the autophagy machinery, promoting selective lysosomal degradation.

References

1. Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease. JAMA Neurology (2024).
2. Targeted degradation of ⍺-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology. Molecular Neurodegeneration (2023).
3. Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue. Nature Communications (2024).
4. α-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis. Translational Neurodegeneration (2023).
5. Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel. Nature Communications (2018).
6. α-Synuclein Is Degraded by Both Autophagy and the Proteasome*. Journal of Biological Chemistry (2003).
7. Wild Type α-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells*. Journal of Biological Chemistry (2008).
8. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Molecular Neurodegeneration (2012).