title: Differential effects of UCHL1 modulation on alpha-synuclein in PD-like models of alpha-synucleinopathy.
abstract: 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.
authors.affiliation: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Cartier
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Vazquez-Roque
authors.forename: Kori Ann
authors.initials: KA
authors.lastname: Kosberg
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fourgeaud
authors.forename: Priya
authors.initials: P
authors.lastname: Kanayson
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Gentry N
authors.initials: GN
authors.lastname: Patrick
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D043222:Ubiquitin Thiolesterase; D051844:alpha-Synuclein; C496976:Uchl1 protein, mouse