![]() ![]() MA degrades cellular waste after the fusion of the autophagosomes carrying the material with the lysosome containing the enzymatic material. ALP is a cellular proteolytic system which allows the degradation of long-lived proteins, protein aggregates, and abnormal organelles through both macroautophagy (MA) and chaperone-mediated autophagy (CMA) processes. The signals responsible for targeting α-syn to either degradation pathway remain not fully understood.ĪLP was shown to be implicated in the degradation of monomeric, small, soluble oligomeric species, as well as aggregated forms of the α-syn protein. The α-Syn degradation is ensured by both the ubiquitin-proteasome system and by the autophagy-lysosomal pathways (ALP) protein degradation machinery. Although the trigger phenomenon remains to be elucidated, three cellular factors have been suggested to play a role in α-syn aggregation: (i) increased expression of the SNCA gene encoding α-syn, (ii) post-translational modifications or mutations favoring α-syn aggregation, and (iii) impaired α-syn protein degradation. ![]() The α-Syn accumulation leads to the formation of misfolded α-syn species that aggregate in the cytoplasm, forming LB and GCI. Īlthough synucleinopathy regroups heterogenous clinical disorders, the neuropathological common denominator is the accumulation of the 140-amino acid protein, α-syn, in different brain regions of PD, DLB, and MSA patients. As part of synucleinopathy, MSA patients’ brains exhibit α-syn-positive intracytoplasmic inclusions, which accumulate mainly in the oligodendrocytes, called glial cytoplasmic inclusions (GCI). MSA is a rarer synucleinopathy, affecting 1–9/100,000 persons worldwide, divided into two clinical phenotypes: the MSA-parkinsonian with levodopa non-responsiveness parkinsonian syndrome due to neurodegeneration in the nigro-striatal pathway, and the MSA-cerebellar with gait, speech, and limb ataxia, as well as oculomotor dysfunction, due to neurodegeneration in the olivo-pontocerebellar system. DLB patients exhibit neurodegeneration in the SN, as well as LB deposition in the brain, but DLB differs from PD by the presence of amyloid plaques in cortical areas. DLB is the second most prevalent synucleinopathy, clinically characterized by parkinsonian syndrome associated with cognitive deficits. The major neuropathological hallmark of PD is the presence of α-syn-positive intracytoplasmic inclusions called Lewy Bodies (LB), which accumulate in neurons. PD is clinically characterized by a triad of motor symptoms (resting tremor, rigidity, and akinesia) caused by dopaminergic striatal depletion due to the loss of dopaminergic neurons in the substantia nigra (SN). PD is the most prevalent synucleinopathy worldwide, with 1–5% of the population over the age of 60 developing this disease. Synucleinopathies are neurodegenerative diseases characterized by the presence of alpha-synuclein (α-syn)-positive intracytoplasmic inclusions in the central nervous system (CNS), such as Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). ![]()
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