Generation of a alpha-synuclein-based rat model of Parkinson's disease.
Two missense mutations (A30P and A53T) in the gene for alpha-synuclein (alpha-syn) cause familial Parkinson's disease (PD) in a small cohort. There is increasing evidence to propose that abnormal metabolism and accumulation of alpha-syn in dopaminergic neurons play a role in the development of familial as well as sporadic PD. The complexity of the mechanisms underlying alpha-syn-induced neurotoxicity, however, has made difficult the development of animal models that faithfully reproduce human PD pathology. We now describe and characterize such a model, which is based on the stereotaxic injection into rat right substantia nigra pars compacta of the A30P mutated form of alpha-syn fused to a protein transduction domain (TAT). The TAT sequence allows diffusion of the fusion protein across the neuronal plasma membrane and results in a localized dopaminergic loss. Dopaminergic cell loss was evaluated both by tyrosine hydroxylase immunohistochemistry and by HPLC analysis of dopamine and its catabolite 3,4 dihydroxyphenylacetic acid. Infusion of TAT-alpha-synA30P induced a significant 26% loss in dopaminergic neurons. This dopaminergic loss was accompanied by a time-dependent impairment in motor function, evaluated utilizing the rotarod and footprint tests. In comparison to chemical neurotoxin-based (e.g. 6-hyroxydopamine, MPTP) animal models of PD, the alpha-syn-based PD animal model offers the advantage of mimicking the early stages and slow development of the human disease and should prove valuable in assessing specific aspects of PD pathogenesis in vivo and in developing new therapeutic strategies.
Recchia
Alessandra
A
Department of Pharmacology and Anesthesiology, University of Padua, Largo Meneghetti, 2, 35131 Padua, Italy.
Rota
David
D
Debetto
Patrizia
P
Peroni
Daniele
D
Guidolin
Diego
D
Negro
Alessandro
A
Skaper
Stephen D
SD
Giusti
Pietro
P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage; D005786:Gene Expression Regulation; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D018663:Adrenergic Agents; D018491:Dopamine Agonists; D015696:Gene Products, tat; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; D049452:Green Fluorescent Proteins; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine