Tags

Type your tag names separated by a space and hit enter

Participation of par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid.
Exp Neurol. 2000 Sep; 165(1):1-11.EN

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and dementia. It is caused by a polyglutamine repeat expansion in the huntingtin protein. The striatum is a major site of neuronal loss in HD, but the mechanisms underlying the neurodegenerative process have not been established. Systemic administration of the succinate dehydrogenase inhibitor 3-nitropropionic acid (3NP) to rodents results in motor dysfunction and degeneration of striatal neurons with features similar to those of HD. Here we report that levels of prostate apoptosis response-4 (Par-4; a protein recently linked to neuronal apoptosis) increase in striatum, and to a lesser extent in cortex and hippocampus, after systemic administration of 3NP to adult rats. The increase in Par-4 levels occurred within 6 h of 3NP administration and was followed by an increase in caspase activation which preceded neuronal loss. Exposure of cultured primary striatal neurons to 3NP induced a rapid increase of Par-4 levels and caspase activation. Treatment of striatal neurons with a Par-4 antisense oligonucleotide blocked Par-4 induction by 3NP, suppressed caspase activation, and attenuated neuronal apoptosis. The caspase-3 inhibitor DEVD suppressed 3NP-induced apoptosis of striatal neurons, but did not prevent induction of Par-4, indicating that Par-4 acts upstream of caspase-3 activation in the cell death pathway. Our results suggest that Par-4 plays an important role in the degeneration of striatal neurons in an experimental model of HD.

Authors+Show Affiliations

Department of Anatomy & Neurobiology, Sanders-Brown Center on Aging, Lexington, Kentucky 40536, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

10964480

Citation

Duan, W, et al. "Participation of Par-4 in the Degeneration of Striatal Neurons Induced By Metabolic Compromise With 3-nitropropionic Acid." Experimental Neurology, vol. 165, no. 1, 2000, pp. 1-11.
Duan W, Guo Z, Mattson MP. Participation of par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid. Exp Neurol. 2000;165(1):1-11.
Duan, W., Guo, Z., & Mattson, M. P. (2000). Participation of par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid. Experimental Neurology, 165(1), 1-11.
Duan W, Guo Z, Mattson MP. Participation of Par-4 in the Degeneration of Striatal Neurons Induced By Metabolic Compromise With 3-nitropropionic Acid. Exp Neurol. 2000;165(1):1-11. PubMed PMID: 10964480.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Participation of par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid. AU - Duan,W, AU - Guo,Z, AU - Mattson,M P, PY - 2000/8/31/pubmed PY - 2000/10/7/medline PY - 2000/8/31/entrez SP - 1 EP - 11 JF - Experimental neurology JO - Exp Neurol VL - 165 IS - 1 N2 - Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and dementia. It is caused by a polyglutamine repeat expansion in the huntingtin protein. The striatum is a major site of neuronal loss in HD, but the mechanisms underlying the neurodegenerative process have not been established. Systemic administration of the succinate dehydrogenase inhibitor 3-nitropropionic acid (3NP) to rodents results in motor dysfunction and degeneration of striatal neurons with features similar to those of HD. Here we report that levels of prostate apoptosis response-4 (Par-4; a protein recently linked to neuronal apoptosis) increase in striatum, and to a lesser extent in cortex and hippocampus, after systemic administration of 3NP to adult rats. The increase in Par-4 levels occurred within 6 h of 3NP administration and was followed by an increase in caspase activation which preceded neuronal loss. Exposure of cultured primary striatal neurons to 3NP induced a rapid increase of Par-4 levels and caspase activation. Treatment of striatal neurons with a Par-4 antisense oligonucleotide blocked Par-4 induction by 3NP, suppressed caspase activation, and attenuated neuronal apoptosis. The caspase-3 inhibitor DEVD suppressed 3NP-induced apoptosis of striatal neurons, but did not prevent induction of Par-4, indicating that Par-4 acts upstream of caspase-3 activation in the cell death pathway. Our results suggest that Par-4 plays an important role in the degeneration of striatal neurons in an experimental model of HD. SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/10964480/Participation_of_par_4_in_the_degeneration_of_striatal_neurons_induced_by_metabolic_compromise_with_3_nitropropionic_acid_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(00)97434-X DB - PRIME DP - Unbound Medicine ER -