Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice.
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.
Gomez-Isla
Teresa
T
Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA.
Irizarry
Michael C
MC
Mariash
Ami
A
Cheung
Bonnie
B
Soto
Oscar
O
Schrump
Stefanie
S
Sondel
Jesse
J
Kotilinek
Linda
L
Day
John
J
Schwarzschild
Michael A
MA
Cha
Jang-Ho J
JH
Newell
Kathy
K
Miller
David W
DW
Uéda
Kenji
K
Young
Anne B
AB
Hyman
Bradley T
BT
Ashe
Karen H
KH
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
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