Transduced Tat-alpha-synuclein protects against oxidative stress in vitro and in vivo.
Parkinson's disease (PD) is a common neurodegenerative disorder and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Although many studies showed that the aggregation of alpha-synuclein might be involved in the pathogenesis of PD, its protective properties against oxidative stress remain to be elucidated. In this study, human wild type and mutant alpha-synuclein genes were fused with a gene fragment encoding the nine amino acid transactivator of transcription (Tat) protein transduction domain of HIV-1 in a bacterial expression vector to produce a genetic in-frame WT Tat-alpha-synuclein (wild type) and mutant Tat-alpha-synucleins (mutants; A30P and A53T), respectively, and we investigated the protective effects of wild type and mutant Tat-alpha-synucleins in vitro and in vivo. WT Tat-alpha-synuclein rapidly transduced into an astrocyte cells and protected the cells against paraquat induced cell death. However, mutant Tat-alpha-synucleins did not protect at all. In the mice models exposed to the herbicide paraquat, the WT Tat-alpha-synuclein completely protected against dopaminergic neuronal cell death, whereas mutants failed in protecting against oxidative stress. We found that these protective effects were characterized by increasing the expression level of heat shock protein 70 (HSP70) in the neuronal cells and this expression level was dependent on the concentration of transduced WT Tat-alpha-synuclein. These results suggest that transduced Tat-alpha-synuclein might protect cell death from oxidative stress by increasing the expression level of HSP70 in vitro and in vivo and this may be of potential therapeutic benefit in the pathogenesis of PD.
Choi
Hee Soon
HS
Department of Biomedical Sciences, Hallym University, Chunchon, Korea. sychoi@hallym.ac.kr
Lee
Sun Hwa
SH
Kim
So Young
SY
An
Jae Jin
JJ
Hwang
Seok Il
SI
Kim
Dae Won
DW
Yoo
Ki Yeon
KY
Won
Moo Ho
MH
Kang
Tae Cheon
TC
Kwon
Hyung Joo
HJ
Kang
Jung Hoon
JH
Cho
Sung Woo
SW
Kwon
Oh Shin
OS
Choi
Jin Hi
JH
Park
Jinseu
J
Eum
Won Sik
WS
Choi
Soo Young
SY
D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D016923:Cell Death; D002470:Cell Survival; D015696:Gene Products, tat / Q000235:genetics; D005822:Genetic Vectors; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009410:Nerve Degeneration / Q000517:prevention & control; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010269:Paraquat; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology; D021381:Protein Transport; D011993:Recombinant Fusion Proteins; D014161:Transduction, Genetic; D051844:alpha-Synuclein / Q000235:genetics / Q000502:physiology*
D015696:Gene Products, tat; D018840:HSP70 Heat-Shock Proteins; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; D010269:Paraquat