title: Long-term protective effects of AAV9-mesencephalic astrocyte-derived neurotrophic factor gene transfer in parkinsonian rats.
abstract: Intrastriatal injection of mesencephalic astrocyte-derived neurotrophic factor (MANF) protein has been shown to provide neuroprotective and neurorestorative effects in a 6-hydroxydopamine (6-OHDA) - lesioned rat model of Parkinson's disease. Here, we used an adeno-associated virus serotype 9 (AAV9) vector to deliver the human MANF (hMANF) gene into the rat striatum 10days after a 6-OHDA lesion to examine long-term effects of hMANF on nigral dopaminergic neurons and mechanisms underlying MANF neuroprotection. Intrastriatal injection of AAV9-hMANF vectors led to a robust and widespread expression of the hMANF gene in the injected striatum up to 24weeks. Increased levels of hMANF protein were also detected in the ipsilateral substantia nigra. The hMANF gene transfer promoted the survival of nigral dopaminergic neurons, regeneration of striatal dopaminergic fibers and an upregulation of striatal dopamine levels, resulting in a long-term improvement of rotational behavior up to 16weeks after viral injections. By using SH-SY5Y cells, we found that intra- and extracellular application of MANF protected cells against 6-OHDA-induced toxicity via inhibiting the endoplasmic reticulum stress and activating the PI3K/Akt/mTOR pathway. Our results suggest that AAV9-mediated hMANF gene delivery into the striatum exerts long-term neuroprotective and neuroregenerative effects on the nigrostriatal dopaminergic system in parkinsonian rats, and provide insights into mechanisms responsible for MANF neuroprotection.
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Hao
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Capital Medical University, Beijing 100069, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Hoffer
authors.affiliation: Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: Zhao
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China; Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China; Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Cleveland, OH 44122, USA. Electronic address: duanwm08@yahoo.com.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Duan
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China; Department of Neurobiology, Capital Medical University, Beijing 100069, China; Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing 100069, China; Beijing Center of Neural Regeneration and Repair, Beijing 100069, China; Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing 100069, China. Electronic address: xuqy@ccmu.edu.cn.
authors.forename: Qun-Yuan
authors.initials: QY
authors.lastname: Xu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D018663:Adrenergic Agents / Q000633:toxicity; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D018014:Gene Transfer Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009410:Nerve Degeneration / Q000209:etiology / Q000628:therapy; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; C099695:MANF protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Adeno-associated virus vectors; Dopaminergic neurons; Endoplasmic reticulum stress; Gene transfer; Mesencephalic astrocyte-derived neurotrophic factor; PI3K/Akt/mTOR pathway; Parkinson's disease