Biomedical Research Foundation Academy Of AthensAcademy Of Athens
Research Highlights :Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats

Most cells have certain components that are either unnecessary or dysfunctional. Autophagy is the natural process that rids the cell of these harmful components by either disassembling or recycling them. This process encompasses the delivery of intracellular constituents into the lysosomes and the subsequent reutilization of the resultant building blocks.

Chaperone-mediated autophagy (CMA) is one of the three forms of autophagy, and the only one that is able to selectively degrade certain proteins inside the lysosomes. One of the well-known substrates of the CMA pathway is the neuronal protein Synuclein alpha (SNCA) that plays a crucial role in Parkinson’s disease (PD) pathogenesis.

In a study published in Autophagy, the authors uncovered the important role of the CMA pathway in certain brain areas, particularly in the adult dopaminergic system, which is mainly affected in PD. The researchers in the Stefanis & Xilouri Groups inhibited the CMA pathway selectively in dopaminergic neurons and detected symptoms of PD in the affected neurons.

Specifically, in the current study, CMA inhibition in the adult rat substantia nigra was achieved via adeno-associated virus-mediated delivery of short hairpin RNAs targeting the LAMP2A receptor, CMA’s rate limiting step; such CMA inhibition 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 down-regulation resulted in progressive loss of nigral dopaminergic neurons, severe reduction in striatal dopamine levels/terminals, increased astro- and micro- gliosis and relevant motor deficits.

Thus, the presented model of LAMP2A down-regulation in the adult substantia nigra recapitulates the main features of PD, including the severe loss of dopaminergic neurons and the accumulation of ubiquitinated SNCA within surviving neurons. This novel PD animal model may be useful in investigating relevant mechanisms and therapeutic interventions.


Xilouri M, Brekk OR, Polissidis A, Chrysanthou-Piterou M, Kloukina I, Stefanis L. Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats. Autophagy. 2016 Aug 19:0. [Epub ahead of print] PMID: 27541985