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Biomedical sciences publications November 1, 2014

miRNA and Autophagy in the Pharmacological Gaucher Mouse Model

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Mak, S. K., Ko, N., Chou, V. P., Di Monte, D. A., & Manning-Bog, A. (2014, 15-19 November). miRNA and autophagy in the pharmacological Gaucher mouse model. Paper presented at Neuroscience 2014, Washington, DC.

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).

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