title: Down-regulation of alpha-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson's disease rat model.
abstract: Fibrillization and aggregation of alpha-synuclein may play a critical role in neurodegenerative diseases like Parkinson's diseases. Adeno-associated virus (AAV) vector delivery of an alpha-synuclein ribozyme was tested for its silencing effect on degenerating nigrostriatal neurons in the MPP(+) model of Parkinson's disease. We designed alpha-synuclein ribozyme against human alpha-synuclein gene expression and constructed alpha-synuclein ribozymes-carrying rAAV vector (designated rAAV-SynRz). Co-transfection of rAAV-SynRz and rAAV-alpha-synuclein into HEK293 cells resulted in down-regulation of alpha-synuclein protein expression in vitro. Then, rAAV-SynRz was injected into the substantia nigra (SN) of MPP(+)-treated rats. Cell counts of TH-positive neurons in the SN revealed that rAAV-SynRz significantly protected TH-positive cells against apoptotic death, compared with those of rAAV-EGFP or no rAAV injected rats. Our results indicate that the use of rAAV-SynRz allowed the survival of higher number of TH-positive neurons in SN in the MPP(+) model. Down-regulation of alpha-synuclein expression could be potentially a suitable target for gene therapy of Parkinson's disease.
authors.affiliation: Research Institute for Diseases of Old Age, Juntendo University, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hayashita-Kinoh
authors.forename: Masanori
authors.initials: M
authors.lastname: Yamada
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002460:Cell Line; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D009474:Neurons / Q000502:physiology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D011726:Pyridinium Compounds; D016337:RNA, Catalytic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D011726:Pyridinium Compounds; D016337:RNA, Catalytic; D051844:alpha-Synuclein; C427204:hammerhead ribozyme; C014677:1-methylpyridinium; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine