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Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP.
Exp Neurol. 2004 Apr; 186(2):158-72.EN

Abstract

Recent studies have implicated alpha-synuclein (alpha-S) in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying PD are not completely understood; however, mitochondrial complex I inhibition and oxidative injury may be involved. Because the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent complex I inhibitor that can cause oxidative injury and mimic many aspects of PD in treated animals, we sought to determine whether the overexpression of alpha-S in transgenic (tg) mice (alpha-S-tg) would enhance the substantia nigra (SN) pathology resulting from treatment with MPTP. For this purpose, alpha-S-tg mice were produced expressing high levels of wild-type (wt) human alpha-S under the control of the neuron-specific Thy-1 promoter. Alpha-S-tg mice and non-tg controls were treated with MPTP (15 mg/kg ip, twice a week for 2 weeks) or saline (Sal) and then examined 2 weeks after completion of treatment by transmission electron microscopy (EM). We found that alpha-S-tg mice treated with MPTP had extensive mitochondrial alterations, increases in mitochondrial size, filamentous neuritic aggregations, axonal degeneration, and formation of electron dense perinuclear cytoplasmic inclusions in the SN that did not occur in the hippocampus or neocortex, nor in MPTP-treated non-tg mice or Sal-treated alpha-S-tg mice. These findings support the potential involvement of alpha-S expression in the vulnerability of SN neurons to toxicity from mitochondrial complex I inhibitors and the subsequent development of neurodegenerative pathology.

Authors+Show Affiliations

Neurology Service, VA San Diego Healthcare System, San Diego, CA 92161-9127, USA. dsong@vapop.ucsd.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15026254

Citation

Song, David D., et al. "Enhanced Substantia Nigra Mitochondrial Pathology in Human Alpha-synuclein Transgenic Mice After Treatment With MPTP." Experimental Neurology, vol. 186, no. 2, 2004, pp. 158-72.
Song DD, Shults CW, Sisk A, et al. Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp Neurol. 2004;186(2):158-72.
Song, D. D., Shults, C. W., Sisk, A., Rockenstein, E., & Masliah, E. (2004). Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Experimental Neurology, 186(2), 158-72.
Song DD, et al. Enhanced Substantia Nigra Mitochondrial Pathology in Human Alpha-synuclein Transgenic Mice After Treatment With MPTP. Exp Neurol. 2004;186(2):158-72. PubMed PMID: 15026254.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. AU - Song,David D, AU - Shults,Clifford W, AU - Sisk,Abbyann, AU - Rockenstein,Edward, AU - Masliah,Eliezer, PY - 2002/12/17/received PY - 2003/06/16/revised PY - 2003/07/02/accepted PY - 2004/3/18/pubmed PY - 2004/4/27/medline PY - 2004/3/18/entrez SP - 158 EP - 72 JF - Experimental neurology JO - Exp Neurol VL - 186 IS - 2 N2 - Recent studies have implicated alpha-synuclein (alpha-S) in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying PD are not completely understood; however, mitochondrial complex I inhibition and oxidative injury may be involved. Because the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent complex I inhibitor that can cause oxidative injury and mimic many aspects of PD in treated animals, we sought to determine whether the overexpression of alpha-S in transgenic (tg) mice (alpha-S-tg) would enhance the substantia nigra (SN) pathology resulting from treatment with MPTP. For this purpose, alpha-S-tg mice were produced expressing high levels of wild-type (wt) human alpha-S under the control of the neuron-specific Thy-1 promoter. Alpha-S-tg mice and non-tg controls were treated with MPTP (15 mg/kg ip, twice a week for 2 weeks) or saline (Sal) and then examined 2 weeks after completion of treatment by transmission electron microscopy (EM). We found that alpha-S-tg mice treated with MPTP had extensive mitochondrial alterations, increases in mitochondrial size, filamentous neuritic aggregations, axonal degeneration, and formation of electron dense perinuclear cytoplasmic inclusions in the SN that did not occur in the hippocampus or neocortex, nor in MPTP-treated non-tg mice or Sal-treated alpha-S-tg mice. These findings support the potential involvement of alpha-S expression in the vulnerability of SN neurons to toxicity from mitochondrial complex I inhibitors and the subsequent development of neurodegenerative pathology. SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/15026254/Enhanced_substantia_nigra_mitochondrial_pathology_in_human_alpha_synuclein_transgenic_mice_after_treatment_with_MPTP_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S001448860300342X DB - PRIME DP - Unbound Medicine ER -