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Excess ?-synuclein worsens disease in mice lacking ubiquitin carboxy-terminal hydrolase L1.

ABSTRACT: Mutations in ?-synuclein (?SN) 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. ?SN 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 ?SN 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 ?SN are not accompanied by microgliosis, ubiquitin pathology or changes in pathological ?SN protein levels and species.

SUBMITTER: Shimshek DR

PROVIDER: S-EPMC3278044 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Excess α-synuclein worsens disease in mice lacking ubiquitin carboxy-terminal hydrolase L1.

Shimshek Derya R DR Schweizer Tatjana T Schmid Peter P van der Putten P Herman PH

Scientific reports 20120213

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 i ...[more]

PMID: 22355774

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