title: Excess α-synuclein worsens disease in mice lacking ubiquitin carboxy-terminal hydrolase L1.
abstract: Mutations in α-synuclein (αSN) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have been linked to familial Parkinson's disease (PD). Physical and functional interactions between these two proteins have been described. Whether they act additively in vivo to influence disease has remained controversial. αSN is a presynaptic protein and the major constituent of Lewy inclusions, histopathological hallmarks of PD. UCH-L1 regulates ubiquitin stability in the nervous system and its loss results in neurodegeneration in peripheral and central neurons. Here, we used genetics to show that UCH-L1-deficiency together with excess αSN worsen disease. Double mutant mice show earlier-onset motor deficits, a shorter lifespan and forebrain astrogliosis but the additive disease-worsening effects of UCH-L1-deficiency and excess αSN are not accompanied by microgliosis, ubiquitin pathology or changes in pathological αSN protein levels and species.
authors.affiliation: Neuroscience Research, Novartis Institutes for BioMedical Research , Novartis Pharma AG, 4002 Basel, Switzerland. derya.shimshek@novartis.com
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
authors.forename: Tatjana
authors.initials: T
authors.lastname: Schweizer
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
authors.forename: P Herman
authors.initials: PH
authors.lastname: van der Putten
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D043222:Ubiquitin Thiolesterase; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D043222:Ubiquitin Thiolesterase; D051844:alpha-Synuclein; C496976:Uchl1 protein, mouse