miRNA and Autophagy in the Pharmacological Gaucher Mouse Model

Abstract

This study investigates early stage pathogenetic targets that contribute to degeneration in Gaucher disease, Parkinson’s disease (PD) and Gaucher-related PD. Clinical, pathological and experimental evidence provides a link between α-synucleinopathies and lysosomal storage diseases, in particular PD and Gaucher disease. Genetic screens show that GBA mutation carriers are at risk for developing parkinsonism and other α-synucleinopathies, and α-synuclein pathology (i.e. Lewy bodies) are found in post-mortem studies of such cases. Autophagy is a crucial pathway to digest the unwanted proteins to maintain protein homeostasis in the brain. However, if lysosomal clearance were impaired, toxic proteins such as α-synuclein accumulate into dopaminergic neurons and promote neurodegeneration. Here, we utilized a paradigm of glucocerebrosidase deficiency, exposing mice to 100 mg/kg conduritol B epoxide (CBE) or vehicle, i.p., once daily for 21 consecutive days. Preliminary data showed significant activation of chaperone-mediated autophagy (CMA) and macroautophagy and a markedly altered profile of miRNAs in the pharmacological mouse model. Specifically, in CBE-treated mice, an apparent increase in cellular α-synuclein protein in the nigrostriatal pathway with no change in ventral midbrain Snca transcript was detected. These changes were accompanied by significantly increased Lamp2A transcript (~1.6 fold)– indicative of CMA activation–and macroautophagic markers such as Atg3 (~1.8 fold) and Atg12 (~1.4 fold) transcripts. On-going studies will elucidate the impact of miRNA modulation on autophagic dysfunction and α-synuclein pathology related to glucocerebrosidase deficiency. These studies were funded by SRI SBT Award W32MTD (AMB), SRI IR&D Award W32S6X (SKM) and Beatrice & Roy Backus Foundation P21769 (AMB/SKM).