Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5629326 | Experimental Neurology | 2017 | 14 Pages |
â¢Intrastriatal delivery of AAV9-hMANF leads to robust striatal transduction.â¢Intrastriatal delivery of AAV9-hMANF reduces rotational scores of parkinsonian rats.â¢Intrastriatal delivery of AAV9-hMANF promotes the survival of nigral DA neurons.â¢Intracellular overexpression of MANF protects SH-SY5Y cells via inhibiting ER stress.â¢Extracellular rhMANF protein protects SH-SY5Y cells via the PI3K/Akt/mTOR pathway.
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 10Â days 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 24Â weeks. 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 16Â weeks 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.