Proteostasis of α-Synuclein and Its Role in the Pathogenesis of Parkinson’s Disease

Abstract

Aggregation of α-Synuclein, possibly caused by disturbance of proteostasis, has been identified as a common pathological feature of Parkinson's disease (PD). However, the initiating events of aggregation have not been fully illustrated, and this knowledge may be critical to understanding the disease mechanisms of PD. Proteostasis is essential in maintaining normal cellular metabolic functions, which regulate the synthesis, folding, trafficking, and degradation of proteins. The toxicity of the aggregating proteins is dramatically influenced by its physical and physiological status. Genetic mutations may also affect the metastable phase transition of proteins. In addition, neuroinflammation, as well as lipid metabolism and its interaction with α-Synuclein, are likely to contribute to the pathogenesis of PD. In this review article, we will highlight recent progress regarding α-Synuclein proteostasis in the context of PD. We will also discuss how the phase transition status of α-Synuclein could correlate with different functional consequences in PD.

Gut–Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions

“…On the non-motor side, cognitive disturbances, depression, mood deflection, sensory alternations, sleep alternations, autonomic dysfunctions contribute to significant disability. Such widespread clinical spectrum reflects the accumulation of α-synuclein in both central and peripheral nervous system [ 129 , 130 ]. Gastrointestinal (GI) symptoms are experienced by most PD patients.…”

Alternative systems for misfolded protein clearance: life beyond the proteasome

“…Consistent with this model, toxic UBQLN2 mutations found in amyotrophic lateral sclerosis and frontotemporal dementia impair the protein's LLPS properties [177,179]—although this is not sufficient to recapitulate fully the neuronal loss characteristic of the disease [180]. Alteration of LLPS dynamics by disease‐associated amyloidogenic proteins has been added to the growing list of pathogenic drivers in neurodegeneration [181,182], potentially as a result of interfering with nucleocytoplasmic transport at the nuclear pore [183]—a multiprotein assembly that employs phase separation to moderate its permeability barrier [184]. The finding that targeting disease‐associated IPOD substrates to the JUNQ impairs the mobility of other JUNQ‐targeted misfolded proteins and chaperones, and eventually leads to cell death [73,185], suggests that a similar mechanism may be at play at this juxta‐nuclear PQC site.…”

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

“…Besides SNCA , more than 20 PD relate genes have been identified, encompassing LRRK2 , GBA1 , PINK1 , PARK7 , and PARK2 [ 190 , 191 , 192 ]. Not only sporadic but also genetic PD display accumulation of brain αSyn inclusions, and genetic mutations are mostly involved in αSyn aggregation or clearance pathways [ 193 ]. αSyn inclusions are thought to spread along neuronal connections in a stereotypical pattern in the nervous system and pathological forms of αSyn propagate in cell culture models and in vivo in a prion-like manner.…”