PD Guide

PARK5 (UCHL1)

PARK5, PGP9.5, UCHL1, Uch-L1, PGP95
Protein Degradation Pathways, Targeting Protein Degradation Pathways

A possible causal mutation (I93M) in the gene for ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a neuronal-specific ubiquitin hydrolase/ligase, was identified in two siblings of a German family. Clinically, both siblings exhibited features similar to idiopathic PD, with age of onset around 50 years (Leroy et al., 1998).

Despite being given the PARK5 designation, the mutation has yet to be confirmed by others (Healy et al., 2004). Some studies have demonstrated that another mutation within this gene (S18Y) reduces risk for PD, but this remains controversial (Maraganore et al., 2004; Healy et al., 2006).

Though not established as a causative factor, identification of UCHL1 supports the ubiquitin/proteosome hypothesis of PD pathogenesis (Cookson, 2005).

Reference: 
Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, et al. The ubiquitin pathway in Parkinson's disease. Nature. 1998;395(6701):451-2.
Healy DG, Abou-Sleiman PM, Wood NW. Genetic causes of Parkinson's disease: UCHL-1. Cell Tissue Res. 2004;318(1):189-94.
Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, Krüger R, et al. UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol. 2004;55(4):512-21.
Healy DG, Abou-Sleiman PM, Casas JP, Ahmadi KR, Lynch T, Gandhi S, et al. UCHL-1 is not a Parkinson's disease susceptibility gene. Ann Neurol. 2006;59(4):627-33.
Cookson MR. The biochemistry of Parkinson's disease. Annu Rev Biochem. 2005;74:29-52.
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Reference:
Healy DG, Abou-Sleiman PM, Casas JP, Ahmadi KR, Lynch T, Gandhi S, et al. UCHL-1 is not a Parkinson's disease susceptibility gene. Ann Neurol. 2006;59(4):627-33.
Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, Krüger R, et al. UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol. 2004;55(4):512-21.
Carmine Belin A, Westerlund M, Bergman O, Nissbrandt H, Lind C, Sydow O, et al. S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinson's disease in Sweden. Parkinsonism Relat Disord. 2007;13(5):295-8.
Elbaz A, Levecque C, Clavel J, Vidal JS, Richard F, Corrèze JR, et al. S18Y polymorphism in the UCH-L1 gene and Parkinson's disease: evidence for an age-dependent relationship. Mov Disord. 2003;18(2):130-7.
Hutter CM, Samii A, Factor SA, Nutt JG, Higgins DS, Bird TD, et al. Lack of evidence for an association between UCHL1 S18Y and Parkinson's disease. Eur J Neurol. 2008;15(2):134-9.
Zhang Z-, Burgunder J-, An X-, Wu Y, Chen W-, Zhang J-, et al. Lack of evidence for association of a UCH-L1 S18Y polymorphism with Parkinson's disease in a Han-Chinese population. Neurosci Lett. 2008;442(3):200-2.
Ragland M, Hutter C, Zabetian C, Edwards K. Association between the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1) S18Y variant and Parkinson's Disease: a HuGE review and meta-analysis. Am J Epidemiol. 2009;170(11):1344-57.
Zetterberg M, Sjolander A, von Otter M, Seibt Palmer M, Landgren S, Minthon L, et al. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease. Molecular neurodegeneration. 2010;5(1):11.