Initiation and progression of α-synuclein pathology in Parkinson’s disease

Abstract

Abstractα-Synuclein aggregation is a critical molecular process that underpins the pathogenesis of Parkinson’s disease. Aggregates may originate at synaptic terminals as a consequence of aberrant interactions between α-synuclein and lipids or evasion of proteostatic defences. The nature of these interactions is likely to influence the emergence of conformers or strains that in turn could explain the clinical heterogeneity of Parkinson’s disease and related α-synucleinopathies. For neurodegeneration to occur, α-synuclein assemblies need to exhibit seeding competency, i.e. ability to template further aggregation, and toxicity which is at least partly mediated by interference with synaptic vesicle or organelle homeostasis. Given the dynamic and reversible conformational plasticity of α-synuclein, it is possible that seeding competency and cellular toxicity are mediated by assemblies of different structure or size along this continuum. It is currently unknown which α-synuclein assemblies are the most relevant to the human condition but recent advances in the cryo-electron microscopic characterisation of brain-derived fibrils and their assessment in stem cell derived and animal models are likely to facilitate the development of precision therapies or biomarkers. This review summarises the main principles of α-synuclein aggregate initiation and propagation in model systems, and their relevance to clinical translation.

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

“…Abnormal accumulation of α-synuclein [ 15 , 46 ], and in some cases of γ-synuclein [ 47 , 48 ], occurs in synucleinopathies [ 49 ]. Although relatively small α-synuclein oligomers are considered the most toxic species, it is not exactly known which α-synuclein assemblies possess the most toxic properties [ 26 ] and are the most relevant to human diseases. Accumulating data indicate that smaller-size aggregates cause a higher toxic response than filamentous aggregates (fibrils) [ 50 ].…”

“…Intracellular accumulation of prone-to-aggregate proteins associated with the formation of amyloid-like fibrils, is a common neuropathological feature of several neurodegenerative diseases. The “unfolding” of intrinsically disordered proteins is similar to the misfolding of globular proteins [ 26 , 27 ].…”

The emerging role of furin in neurodegenerative and neuropsychiatric diseases

“…PD is the second most common neurodegenerative disorder, pathologically characterized by abnormal deposition of α-synuclein aggregates in Lewy bodies and loss of nigrostriatal DA neurons [ 262 , 263 ]. The striking clinical symptoms of PD are motor symptoms such as tremor, rigidity, bradykinesia and postural instability.…”

Skin alpha-synuclein deposit patterns: A predictor of Parkinson's disease subtypes

“… 1 Toxic oligomers may be the primary cause of neurotoxicity but are not responsible for propagation, as shown by in vitro studies. 7 Fibrils are the elements that propagate in a prion-like manner. 7 Recently, the potential for two-way propagation between the enteric nervous system (ENS) and central nervous system (CNS) was demonstrated.…”

“… 7 Fibrils are the elements that propagate in a prion-like manner. 7 Recently, the potential for two-way propagation between the enteric nervous system (ENS) and central nervous system (CNS) was demonstrated. 8 Pathological biopsies or autopsies of brain tissue from PD patients are not technically difficult, but are obviously not possible in living patients.…”