Parkinson’s disease (PD) is one of the most common progressive neurodegenerative disorders
in modern society. The disease involves many genetic risk factors as well as a sporadic pathogenesis
that is age- and environment-dependent. Of particular interest is the formation of intra-neural
fibrillar aggregates, namely Lewy bodies (LBs), the histological hallmark of PD, which results from
aberrant protein homeostasis or misfolding that results in neurotoxicity. A better understanding of the
molecular mechanism and composition of these cellular inclusions will help shed light on the progression
of misfolding-associated neurodegenerative disorders. Ubiquitin carboxyl-terminal hydrolase
L1 (UCH-L1) is found to co-aggregate with α-synuclein (αS), the major component of LBs.
Several familial mutations of UCH-L1, namely p.Ile93Met (p.I93M), p.Glu7Ala (p.E7A), and
p.Ser18Tyr (p.S18Y), are associated with PD and other neurodegenerative disorders. Here, we review
recent progress and recapitulate the impact of PD-associated mutations of UCH-L1 in the context of
their biological functions gleaned from biochemical and biophysical studies. Finally, we summarize
the effect of these genetic mutations and post-translational modifications on the association of UCHL1
and PD in terms of loss of cellular functions or gain of cellular toxicity.
Keywords: UCH-L1, α-synuclein, Lewy bodies, Parkinson’s disease, ubiquitin, misfolding.
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