Journal Article

Differential Effects of UCHL1 Modulation on Alpha-Synuclein in PD-Like Models of Alpha-Synucleinopathy

Kosberg, Kori Ann, Kanayson, Priya, Masliah, Eliezer, Cartier, Anna E., Rockenstein, Edward, Fourgeaud, Lawrence, Patrick, Christina, Vazquez-Roque, Ruben A., Ubhi, Kiren, Spencer, Brian, Patrick, Gentry N.

2012

Overview

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Abnormal accumulation and aggregation of alpha-synuclein (a-syn) within neurons, and mutations in the a-syn and UCH-L1 genes have been shown to play a role in the pathogenesis of PD. In light of recent reports suggesting an interaction between a-synuclein and UCH-L1, we investigated the effects of UCH-L1 inhibition on a-syn distribution and expression levels in primary neurons and hippocampal tissues derived from non transgenic (non tg) and a-syn over expressing tg mice. We show that suppression of UCH-L1 activity increased a-syn levels in control, non tg neurons, and resulted in a concomitant accumulation of presynaptic a-syn in these neurons. In contrast, blocking UCH-L1 activity in a-syn over expressing neurons decreased a-syn levels, and enhanced its synaptic clearance. In vitro studies verified the LDN-induced inhibition of UCH-L1 had minimal effect on LC3 (a marker of autophagy) in control cells, in cells over expressing a-syn UCH-L1 inhibition resulted in increased LC3 activity. These findings suggest a possible differential role of UCH-L1 function under normal and pathological conditions. Furthermore, in the context of a-syn-induced pathology, modulation of UCH-L1 activity could serve as a therapeutic tool to enhance the autophagy pathway and induce clearance of the observed accumulated/aggregated a-syn species in the PD brain.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Accumulation / alpha-Synuclein - genetics / alpha-Synuclein - metabolism / Animal models / Animal tissues / Animals / Autophagy / Biology / Brain / Cell death / Cell Line, Tumor / Cells, Cultured / Environmental factors / Health aspects / Hippocampus / Hippocampus - cytology / Humans / Huntingtons disease / Immunohistochemistry / Immunoprecipitation / Inhibition / Laboratories / Medicine / Mice / Mice, Transgenic / Modulation / Movement disorders / Mutation / Nervous system diseases / Neurobiology / Neurodegeneration / Neurodegenerative diseases / Neurons / Neurons - enzymology / Neurons - metabolism / Neurosciences / Neurotoxicity / Parkinson Disease - genetics / Parkinson Disease - metabolism / Parkinson's disease / Pathogenesis / Pathology / Phagocytosis / Rats / Synuclein / Transgenic animals / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - metabolism