title: Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice.
abstract: Alpha-synuclein is a major component of Lewy bodies (LBs) in the substantia nigra and cortex in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and in glial inclusions in multiple systems atrophy (MSA). Mutations in alpha-synuclein have been associated with autosomal dominant forms of PD. We investigated the clinical and neuropathological effects of overexpression of human alpha-synuclein, alpha-synuclein A30P, and alpha-synuclein A53T under the control of the hamster prion protein (PrP) promoter; 5-15x endogenous levels of protein expression were achieved with widespread neuronal, including nigral, transgene expression. High expression of alpha-synuclein A30P in the Tg5093 line was associated with a progressive motor disorder with rigidity, dystonia, gait impairment, and tremor. Histological analysis of this line showed aberrant expression of the protein in cell soma and progressive CNS gliosis, but no discrete Lewy body-like alpha-synuclein inclusions could be identified. Biochemical analysis demonstrated alpha-synuclein fragmentation. Despite strong expression of the transgene in the nigra, there was no specific deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) containing neurons, striatal TH immunoreactivity, dopamine levels, or dopamine receptor number and function. Lower expressing lines had no specific behavioral or histopathological phenotype. Thus, high expression of mutant human alpha-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line.
authors.affiliation: Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gomez-Isla
authors.forename: Michael C
authors.initials: MC
authors.lastname: Irizarry
authors.forename: Ami
authors.initials: A
authors.lastname: Mariash
authors.forename: Bonnie
authors.initials: B
authors.lastname: Cheung
authors.forename: Oscar
authors.initials: O
authors.lastname: Soto
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schrump
authors.forename: Jesse
authors.initials: J
authors.lastname: Sondel
authors.forename: Linda
authors.initials: L
authors.lastname: Kotilinek
authors.forename: John
authors.initials: J
authors.lastname: Day
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
authors.forename: Jang-Ho J
authors.initials: JH
authors.lastname: Cha
authors.forename: Kathy
authors.initials: K
authors.lastname: Newell
authors.forename: David W
authors.initials: DW
authors.lastname: Miller
authors.forename: Kenji
authors.initials: K
authors.lastname: Uéda
authors.forename: Anne B
authors.initials: AB
authors.lastname: Young
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Karen H
authors.initials: KH
authors.lastname: Ashe
mesh_terms: D000818:Animals; D015415:Biomarkers; D015153:Blotting, Western; D004298:Dopamine / Q000502:physiology*; D004576:Electromyography; D005260:Female; D015870:Gene Expression; D005911:Gliosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology; D051843:Synucleins; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D051844:alpha-Synuclein
chemical_list: D015415:Biomarkers; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine