PMID- 28131727
OWN - NLM
STAT- MEDLINE
DCOM- 20170516
LR  - 20220410
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 291
DP  - 2017 May
TI  - Long-term protective effects of AAV9-mesencephalic astrocyte-derived neurotrophic 
      factor gene transfer in parkinsonian rats.
PG  - 120-133
LID - S0014-4886(17)30016-X [pii]
LID - 10.1016/j.expneurol.2017.01.008 [doi]
AB  - 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.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Hao, Fei
AU  - Hao F
AD  - Department of Anatomy, Capital Medical University, Beijing 100069, China.
FAU - Yang, Chun
AU  - Yang C
AD  - Department of Anatomy, Capital Medical University, Beijing 100069, China.
FAU - Chen, Sha-Sha
AU  - Chen SS
AD  - Department of Anatomy, Capital Medical University, Beijing 100069, China.
FAU - Wang, Yan-Yan
AU  - Wang YY
AD  - Department of Neurobiology, Capital Medical University, Beijing 100069, China.
FAU - Zhou, Wei
AU  - Zhou W
AD  - Department of Anatomy, Capital Medical University, Beijing 100069, China.
FAU - Hao, Qiang
AU  - Hao Q
AD  - Department of Anatomy, Capital Medical University, Beijing 100069, China.
FAU - Lu, Tao
AU  - Lu T
AD  - Department of Anatomy, Capital Medical University, Beijing 100069, China.
FAU - Hoffer, Barry
AU  - Hoffer B
AD  - Department of Neurosurgery, Case Western Reserve University, Cleveland, OH 44106, 
      USA.
FAU - Zhao, Li-Ru
AU  - Zhao LR
AD  - Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, NY 13210, 
      USA.
FAU - Duan, Wei-Ming
AU  - Duan WM
AD  - 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.
FAU - Xu, Qun-Yuan
AU  - Xu QY
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170125
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Adrenergic Agents)
RN  - 0 (Glial Cell Line-Derived Neurotrophic Factor)
RN  - 0 (MANF protein, human)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Nerve Tissue Proteins)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - CK833KGX7E (Amphetamine)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Adrenergic Agents/toxicity
MH  - Amphetamine/pharmacology
MH  - Animals
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Dopamine/metabolism
MH  - Female
MH  - Gene Expression Regulation/genetics
MH  - *Gene Transfer Techniques
MH  - Glial Cell Line-Derived Neurotrophic Factor/genetics/*metabolism
MH  - Humans
MH  - Nerve Degeneration/etiology/therapy
MH  - Nerve Growth Factors/genetics/*metabolism
MH  - Nerve Tissue Proteins/metabolism
MH  - Neuroblastoma/pathology
MH  - Oxidopamine/toxicity
MH  - Parkinsonian Disorders/chemically induced/complications/pathology/*therapy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Stereotyped Behavior/drug effects/physiology
MH  - Tyrosine 3-Monooxygenase/metabolism
OTO - NOTNLM
OT  - Adeno-associated virus vectors
OT  - Dopaminergic neurons
OT  - Endoplasmic reticulum stress
OT  - Gene transfer
OT  - Mesencephalic astrocyte-derived neurotrophic factor
OT  - PI3K/Akt/mTOR pathway
OT  - Parkinson's disease
EDAT- 2017/01/31 06:00
MHDA- 2017/05/17 06:00
CRDT- 2017/01/30 06:00
PHST- 2016/09/14 00:00 [received]
PHST- 2016/12/27 00:00 [revised]
PHST- 2017/01/17 00:00 [accepted]
PHST- 2017/01/31 06:00 [pubmed]
PHST- 2017/05/17 06:00 [medline]
PHST- 2017/01/30 06:00 [entrez]
AID - S0014-4886(17)30016-X [pii]
AID - 10.1016/j.expneurol.2017.01.008 [doi]
PST - ppublish
SO  - Exp Neurol. 2017 May;291:120-133. doi: 10.1016/j.expneurol.2017.01.008. Epub 2017 
      Jan 25.