Synaptophysin enhances the neuroprotection of VMAT2 in MPP+-induced toxicity in MN9D cells.
The use of the potent neurotoxin MPTP in producing a model for Parkinson's disease (PD) has allowed us to dissect the cellular processes responsible for both selective neuronal vulnerability and neuroprotection in idiopathic PD. It has been suggested that vesicular monoamine transporters (VMATs) play a critical neuroprotective role in MPP+ toxicity. However, little is known about how this detoxificative sequestration in dopaminergic (DAergic) neurons is regulated at the molecular and cellular levels. Using the DAergic cell line MN9D as an in vitro model, we found that overexpression of VMAT2 (a neuronal isoform of VMATs) protects the transformants from MPP+-induced toxicity, consistent with the previous work on fibroblastic CHO cells. We further found that the MN9D cells displayed lower expression levels of secretory vesicle proteins such as synaptophysin. Overexpression of synaptophysin in MN9D cells can significantly increase the resistance of the transformants to MPP+ toxicity. The co-expression of VMAT2 and synaptophysin has shown synergistic protection for the transformants, suggesting a role of synaptophysin in the biogenesis of secretory vesicles and in influencing the targeting of VMAT2 to these vesicles. Our work indicates that both the expression level of VMAT2 and capacity of vesicular packaging of DA are important in protecting DAergic cells from MPP+ toxicity.
Chen
Carol X-Q
CX
Department of Neurology, University of Pittsburgh School of Medicine, W958 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Huang
Steven Y
SY
Zhang
Limei
L
Liu
Yong-Jian
YJ
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism*; D014162:Transfection; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009498:Neurotoxins; C493452:SLC18A2 protein, human; C493454:Slc18a2 protein, rat; D016708:Synaptophysin; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine