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Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease.
Ann Neurol. 1999 Oct; 46(4):587-97.AN

Abstract

Dysfunction and death of midbrain dopaminergic neurons underlies the clinical features of Parkinson's disease (PD). Increasing evidence suggests roles for oxidative stress and a form of cell death called apoptosis in the pathogenesis of PD. We recently identified a 38-kd protein called prostate apoptosis response-4 (Par-4), which is rapidly induced in cultured neurons after exposure to apoptotic insults, and appears to play a necessary role in the cell death process. We now report that Par-4 levels increase dramatically in midbrain dopaminergic neurons of monkeys and mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The increase in Par-4 levels occurs in both neuronal cell bodies in the substantia nigra and their axon terminals in the striatum, and precedes loss of tyrosine hydroxylase immunoreactivity and cell death. In the monkey model, Par-4 levels were also increased in several brain regions (red nucleus, lateral geniculate nucleus, and cerebral cortex) in which functional alterations have previously been documented in PD patients and MPTP-treated monkeys. Exposure of cultured human dopaminergic neural cells to the complex I inhibitor rotenone, or to Fe2+, resulted in Par-4 induction, mitochondrial dysfunction, and subsequent apoptosis. Blockade of Par-4 induction by antisense treatment prevented rotenone- and Fe2+-induced mitochondrial dysfunction and apoptosis demonstrating a critical role for Par-4 in the cell death process. The data suggest that Par-4 may be involved in the neurodegenerative process in PD.

Authors+Show Affiliations

Sanders-Brown Research Center on Aging, and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10514095

Citation

Duan, W, et al. "Participation of Prostate Apoptosis Response-4 in Degeneration of Dopaminergic Neurons in Models of Parkinson's Disease." Annals of Neurology, vol. 46, no. 4, 1999, pp. 587-97.
Duan W, Zhang Z, Gash DM, et al. Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease. Ann Neurol. 1999;46(4):587-97.
Duan, W., Zhang, Z., Gash, D. M., & Mattson, M. P. (1999). Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease. Annals of Neurology, 46(4), 587-97.
Duan W, et al. Participation of Prostate Apoptosis Response-4 in Degeneration of Dopaminergic Neurons in Models of Parkinson's Disease. Ann Neurol. 1999;46(4):587-97. PubMed PMID: 10514095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease. AU - Duan,W, AU - Zhang,Z, AU - Gash,D M, AU - Mattson,M P, PY - 1999/10/8/pubmed PY - 1999/10/8/medline PY - 1999/10/8/entrez SP - 587 EP - 97 JF - Annals of neurology JO - Ann Neurol VL - 46 IS - 4 N2 - Dysfunction and death of midbrain dopaminergic neurons underlies the clinical features of Parkinson's disease (PD). Increasing evidence suggests roles for oxidative stress and a form of cell death called apoptosis in the pathogenesis of PD. We recently identified a 38-kd protein called prostate apoptosis response-4 (Par-4), which is rapidly induced in cultured neurons after exposure to apoptotic insults, and appears to play a necessary role in the cell death process. We now report that Par-4 levels increase dramatically in midbrain dopaminergic neurons of monkeys and mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The increase in Par-4 levels occurs in both neuronal cell bodies in the substantia nigra and their axon terminals in the striatum, and precedes loss of tyrosine hydroxylase immunoreactivity and cell death. In the monkey model, Par-4 levels were also increased in several brain regions (red nucleus, lateral geniculate nucleus, and cerebral cortex) in which functional alterations have previously been documented in PD patients and MPTP-treated monkeys. Exposure of cultured human dopaminergic neural cells to the complex I inhibitor rotenone, or to Fe2+, resulted in Par-4 induction, mitochondrial dysfunction, and subsequent apoptosis. Blockade of Par-4 induction by antisense treatment prevented rotenone- and Fe2+-induced mitochondrial dysfunction and apoptosis demonstrating a critical role for Par-4 in the cell death process. The data suggest that Par-4 may be involved in the neurodegenerative process in PD. SN - 0364-5134 UR - https://www.unboundmedicine.com/medline/citation/10514095/Participation_of_prostate_apoptosis_response_4_in_degeneration_of_dopaminergic_neurons_in_models_of_Parkinson's_disease_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0364-5134&date=1999&volume=46&issue=4&spage=587 DB - PRIME DP - Unbound Medicine ER -