Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats

Abstract

Chaperone-mediated autophagy (CMA) involves the selective lysosomal degradation of cytosolic proteins such as SNCA (synuclein a), a protein strongly implicated in Parkinson disease (PD) pathogenesis. However, the physiological role of CMA and the consequences of CMA failure in the living brain remain elusive. Here we show that CMA inhibition in the adult rat substantia nigra via adeno-associated virusmediated delivery of short hairpin RNAs targeting the LAMP2A receptor, involved in CMA's rate limiting step, was accompanied by intracellular accumulation of SNCA-positive puncta, which were also positive for UBIQUITIN, and in accumulation of autophagic vacuoles within LAMP2A-deficient nigral neurons. Strikingly, LAMP2A downregulation resulted in progressive loss of nigral dopaminergic neurons, severe reduction in striatal dopamine levels/terminals, increased astro-and microgliosis and relevant motor deficits. Thus, this study highlights for the first time the importance of the CMA pathway in the dopaminergic system and suggests that CMA impairment may underlie PD pathogenesis.

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

“…These findings identify cytokine signalling as a potential target for the treatment of PD and DLB through the induction of autophagy. Interestingly, defects in CMA may also be implicated in the development of PD and DLB, as was demonstrated recently in rats 49 . Whether boosting CMA ameliorates the manifestations of disease in animal models of parkinsonism remains to be elucidated.…”

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

“…Reducing the hyperactivated status of IIS–mTOR signalling increases autophagic clearance of these aggregates and rescues memory deficits in mouse models of Alzheimer disease 123,124 . Patients with Parkinson disease have decreased levels of lysosome-associated membrane glycoprotein 2 (LAMP2), which is thought to impair the clearance of α-synuclein aggregates and increase neuronal death 125 . In addition, genetic defects in the parkin and PTEN-induced putative kinase protein 1 (PINK1) proteins (BOX 1) impair autophagic clearance of damaged mitochondria in familial Parkinson disease 120 .…”

Role of Chaperone-Mediated Autophagy Dysfunctions in the Pathogenesis of Parkinson’s Disease

“…The down-regulation of lamp2A receptor resulted in an increased sensitivity to oxidative stressors in mouse fibroblasts (Massey et al, 2006) and in the accumulation of soluble high molecular weight and detergent-insoluble species of asyn in PC12 and SH-SY5Y cells (Vogiatzi et al, 2008). Lamp2A down-regulation also causes a raise in autophagic vacuoles within rats nigral neurons with a progressive loss of the same neurons as well as unilateral motor behavioral deficits (Xilouri et al, 2016). However, other studies failed to report CMA dysfunctions after lamp2 silencing, and a compensatory activation of other proteolytic pathways was reported after the aspecific down-regulation of all lamp2 isoforms (Eskelinen et al, 2004; Rothaug et al, 2015).…”