The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

Abstract

The accumulation and misfolding of α‐synuclein (α‐syn) represent the main pathological hallmark of PD. Overexpression of α‐syn and failure of cellular protein degradation systems play a major role in α‐syn aggregation. The discovery of PD‐associated genes related to the autophagic‐lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α‐syn accumulates, suggesting that a crosstalk between α‐syn aggregation and autophagic‐lysosomal impairment may exist. The understanding of autophagic‐lysosomal pathway dysfunctions’ role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic‐lysosomal pathway impairment and misfolded α‐syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic‐lysosomal pathway restoration as a disease‐modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society

Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein

“…The link between ALP dysfunction and PD is well-established with identification of several PD-associated genes related to the ALP (e.g. LRRK2, VPS35) and evidence from cellular and animal models that misfolded forms of α-synuclein lead to ALP dysfunction (Reviewed in [3]). Technical limitations, such as probe specificity and signal detection in brain tissue, restrict the viability of pursuing an option to directly compare and/or dissect the relative contribution of the UPS versus ALP pathways in the degradation of α-synuclein.…”

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

“…The interest of ceramide metabolism in lysosomes goes back to more than 50 years ago when De Duve and Wattiaux [16] had recognized that several lysosomal diseases arise from deficiencies in enzymes involved in the breakdown of simple and complex SphLs. Subsequently, Weinreb et al [17] identified the highest specific activity of acid SMase (aSMase), glucocerebrosidase (GBA), and galactocerbrosidase (GALC) in lysosomes.…”

“…In 2009, a large multicenter analysis, on more than 5000 PD patients and healthy controls showed that mutations on the GBA gene are the most common genetic risk factors for PD [14]. GBA mutations account for 10%-15% of PD patients and this percentage increases to 25% in the Ashkenazi Jewish population [15,16]. Although GBA mutation carriers have 5-6 fold increased risk to develop PD [14], the penetrance of PD in these people is low (from 7.6% at 50 years, to 29.7% at 80 years), thus suggesting that there are other genetic or environmental factors involved in this neurodegenerative process [17].…”

“…To date, the mechanism by which mutated GBA leads to neurodegeneration has not been elucidated; however, data supporting a loss of GBA function as well as a gain of toxic function mechanisms have been published. Several studies carried out on cellular and animal models of both GD and PD, as well as analysis in different cohorts of patients affected by PD, have highlighted the existence of a vicious cycle between GBA dysfunction and α-syn accumulation [16]. In brain tissues of GD patients, immunohistochemical analysis revealed the presence of aggregated α-syn and LBs [28].…”

RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology

“…It has been extensively reported that both aSyn and LRRK2 affect the autophagic process (Bellomo et al, 2020;Bravo-San Pedro et al, 2013;Ho et al, 2019;Schapansky et al, 2014).…”