title: Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies.
abstract: Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and alpha-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.
authors.affiliation: School of Biomedical Sciences and School of Molecular Medical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom.
authors.forename: Lynn
authors.initials: L
authors.lastname: Bedford
authors.forename: David
authors.initials: D
authors.lastname: Hay
authors.forename: Anny
authors.initials: A
authors.lastname: Devoy
authors.forename: Simon
authors.initials: S
authors.lastname: Paine
authors.forename: Des G
authors.initials: DG
authors.lastname: Powe
authors.forename: Rashmi
authors.initials: R
authors.lastname: Seth
authors.forename: Trevor
authors.initials: T
authors.lastname: Gray
authors.forename: Ian
authors.initials: I
authors.lastname: Topham
authors.forename: Kevin
authors.initials: K
authors.lastname: Fone
authors.forename: Nooshin
authors.initials: N
authors.lastname: Rezvani
authors.forename: Maureen
authors.initials: M
authors.lastname: Mee
authors.forename: Tim
authors.initials: T
authors.lastname: Soane
authors.forename: Robert
authors.initials: R
authors.lastname: Layfield
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sheppard
authors.forename: Ted
authors.initials: T
authors.lastname: Ebendal
authors.forename: Dmitry
authors.initials: D
authors.lastname: Usoskin
authors.forename: James
authors.initials: J
authors.lastname: Lowe
authors.forename: R John
authors.initials: RJ
authors.lastname: Mayer
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016631:Lewy Bodies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease