title: Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice.
abstract: Oxidative stress, ubiquitination defects and mitochondrial dysfunction are commonly associated with neurodegeneration. Mice lacking mahogunin ring finger-1 (MGRN1) or attractin (ATRN) develop age-dependent spongiform neurodegeneration through an unknown mechanism. It has been suggested that they act in a common pathway. As MGRN1 is an E3 ubiquitin ligase, proteomic analysis of Mgrn1 mutant and control brains was performed to explore the hypothesis that loss of MGRN1 causes neurodegeneration via accumulation of its substrates. Many mitochondrial proteins were reduced in Mgrn1 mutants. Subsequent assays confirmed significantly reduced mitochondrial complex IV expression and activity as well as increased oxidative stress in mutant brains. Mitochondrial dysfunction was obvious many months before onset of vacuolation, implicating this as a causative factor. Compatible with the hypothesis that ATRN and MGRN1 act in the same pathway, mitochondrial dysfunction and increased oxidative stress were also observed in the brains of Atrn mutants. Our results suggest that the study of Mgrn1 and Atrn mutant mice will provide insight into a causative molecular mechanism common to many neurodegenerative disorders.
authors.affiliation: T2 006B Veterinary Research Tower, Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Kaihua
authors.initials: K
authors.lastname: Sun
authors.forename: Brian S
authors.initials: BS
authors.lastname: Johnson
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Gunn
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D013379:Substrate Specificity / Q000235:genetics; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*
chemical_list: C470689:Mgrn1 protein, mouse; D044767:Ubiquitin-Protein Ligases