title: Aberrant molecular properties shared by familial Parkinson's disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. The I93M mutation in ubiquitin C-terminal hydrolase L1 (UCH-L1) is associated with familial PD, and we have previously shown that the I93M UCH-L1-transgenic mice exhibit dopaminergic cell loss. Over 90% of neurodegenerative diseases, including PD, occur sporadically. However, the molecular mechanisms underlying sporadic PD as well as PD associated with I93M UCH-L1 are largely unknown. UCH-L1 is abundant (1-5% of total soluble protein) in the brain and is a major target of oxidative/carbonyl damage associated with sporadic PD. As well, abnormal microtubule dynamics and tubulin polymerization are associated with several neurodegenerative diseases including frontotemporal dementia and parkinsonism linked to chromosome 17. Here we show that familial PD-associated mutant UCH-L1 and carbonyl-modified UCH-L1 display shared aberrant properties: compared with wild-type UCH-L1, they exhibit increased insolubility and elevated interactions with multiple proteins, which are characteristics of several neurodegenerative diseases-linked mutants. Circular dichroism analyses suggest similar structural changes in both UCH-L1 variants. We further report that one of the proteins interacting with UCH-L1 is tubulin, and that aberrant interaction of mutant or carbonyl-modified UCH-L1 with tubulin modulates tubulin polymerization. These findings may underlie the toxic gain of function by mutant UCH-L1 in familial PD. Our results also suggest that the carbonyl modification of UCH-L1 and subsequent abnormal interactions of carbonyl-modified UCH-L1 with multiple proteins, including tubulin, constitute one of the causes of sporadic PD.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan. kabuta@ncnp.go.jp
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kabuta
authors.forename: Rieko
authors.initials: R
authors.lastname: Setsuie
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mitsui
authors.forename: Aiko
authors.initials: A
authors.lastname: Kinugawa
authors.forename: Mikako
authors.initials: M
authors.lastname: Sakurai
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Aoki
authors.forename: Kenko
authors.initials: K
authors.lastname: Uchida
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002942:Circular Dichroism; D003545:Cysteine / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D050050:Protein Carbonylation; D011499:Protein Processing, Post-Translational; D014404:Tubulin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D014404:Tubulin; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase; C027576:4-hydroxy-2-nonenal; D003545:Cysteine