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Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice
Kaihua Sun1, Brian S Johnson, Teresa M Gunn
1T2 006B Veterinary Research Tower, Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
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.
Insights
Mice lacking mahogunin ring finger-1 (MGRN1) or attractin (ATRN) show mitochondrial dysfunction and oxidative stress, leading to neurodegeneration. These findings suggest a common pathway underlying various neurodegenerative disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Neurodegeneration is linked to oxidative stress, ubiquitination defects, and mitochondrial dysfunction.
- Mahogunin ring finger-1 (MGRN1) and attractin (ATRN) mutations cause age-dependent spongiform neurodegeneration.
- MGRN1 functions as an E3 ubiquitin ligase, suggesting its role in protein degradation pathways.
Purpose of the Study:
- To investigate the molecular mechanism underlying MGRN1- and ATRN-associated neurodegeneration.
- To test the hypothesis that loss of MGRN1 leads to neurodegeneration through substrate accumulation.
- To explore a potential common pathway involving MGRN1 and ATRN in neurodegenerative processes.
Main Methods:
- Proteomic analysis of MGRN1 mutant and control mouse brains.
- Assays to measure mitochondrial complex IV expression and activity.
- Assessment of oxidative stress markers in mutant and control brains.
Main Results:
- Reduced expression of numerous mitochondrial proteins in MGRN1 mutants.
- Significantly decreased mitochondrial complex IV expression and activity in MGRN1 mutants.
- Increased oxidative stress observed in both MGRN1 and ATRN mutant brains, preceding vacuolation.
Conclusions:
- Loss of MGRN1 function leads to mitochondrial dysfunction and oxidative stress, causative factors in neurodegeneration.
- Mitochondrial dysfunction is an early event in the pathogenesis of MGRN1- and ATRN-associated neurodegeneration.
- MGRN1 and ATRN likely act in a common pathway, offering insights into mechanisms shared by multiple neurodegenerative disorders.
