Alpha-Synuclein Pathology in Neurodegenerative Disorders

Alpha-synuclein is a presynaptic protein that adopts multiple conformations, from disordered monomers to various oligomeric and fibrillar assemblies. Under pathological conditions, aberrant folding and aggregation of alpha-synuclein give rise to intracellular inclusions known as Lewy bodies and Lewy neurites, which are hallmarks of Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. Aggregated species disrupt synaptic transmission, mitochondrial function and proteostasis, and may spread via prion-like mechanisms through connected neural circuits. Recent work has revealed molecular signatures of vulnerable neuronal populations, uncovered the role of dynamic tetramer–monomer equilibria in disease initiation and illuminated vascular and glial contributions to cognitive decline. An integrated understanding of these processes is critical for the development of biomarkers and targeted therapies that intervene at early stages of aggregation or block the propagation of toxic species.

Research from Nature Portfolio

Recent studies have mapped the transcriptomic landscape of cortical neurons bearing alpha-synuclein aggregates, identifying a conserved Lewy-associated molecular dysfunction signature. This signature comprises downregulation of synaptic, mitochondrial, proteasomal and cytoskeletal genes alongside upregulation of DNA repair and inflammatory pathways, highlighting common stress responses in both human disease and animal models. In parallel, foundational work on the native state of alpha-synuclein has demonstrated that physiological tetramers can shift towards monomeric forms in the presence of Parkinson’s-related point mutations. This shift destabilises the helical tetramer and promotes pathogenic aggregation, suggesting that stabilising tetramers may represent a novel therapeutic strategy to prevent disease initiation.

Alpha-Synuclein Pathology in Neurodegenerative Disorders publication trend

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

Technical terms

Alpha-synuclein: Neuronal protein prone to misfolding and aggregation, central to several neurodegenerative disorders.

Lewy body: Intracellular inclusion composed largely of aggregated alpha-synuclein, found in Parkinson’s disease and related α-synucleinopathies.

Oligomer: Small assembly of misfolded protein subunits, often more cytotoxic than larger fibrils.

Spatial transcriptomics: Method for mapping gene expression to precise locations within tissue sections.

Induced pluripotent stem cell (iPSC): Somatic cell reprogrammed to a pluripotent state, capable of differentiating into diverse neuronal subtypes.

References

1. α-Synuclein in Central Nervous System and from Erythrocytes, Mammalian Cells, and Escherichia coli Exists Predominantly as Disordered Monomer*. Journal of Biological Chemistry (2012).
2. Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders. Frontiers in Neuroscience (2016).
3. Pathological alpha-synuclein propagates through neural networks. Acta Neuropathologica Communications (2014).
4. Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology. Nature Communications (2024).
5. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nature Communications (2015).
6. Cerebral Microvascular Injury Induced by Lag3‐Dependent α‐Synuclein Fibril Endocytosis Exacerbates Cognitive Impairment in a Mouse Model of α‐Synucleinopathies. Advanced Science (2023).
7. Single-Molecule Detection of α‑Synuclein Oligomers in Parkinson’s Disease Patients Using Nanopores. ACS Nano (2023).
8. Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions. Neuron (2024).