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Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral
Cheolwha Jung1, Cynthia M J Higgins, Zuoshang Xu
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Journal of Neurochemistry
|October 23, 2002
Summary
Mitochondrial dysfunction, specifically decreased enzyme activity in the spinal cord's ventral horn, is evident early in mutant SOD1-linked amyotrophic lateral sclerosis (ALS) progression in mice, indicating a role for mitochondrial damage in motoneuron degeneration.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motoneuron loss.
- Mutations in Cu,Zn superoxide dismutase (SOD1) are a known cause of inherited ALS.
- In mouse models, mutant SOD1 expression leads to motoneuron degeneration and paralysis, mirroring human ALS pathology.
Purpose of the Study:
- To investigate alterations in mitochondrial function during the progression of mutant SOD1-induced ALS.
- To determine if mitochondrial electron transport chain (ETC) enzyme activities are affected in affected spinal cord regions.
Main Methods:
- Enzyme activities of the mitochondrial ETC were measured in mouse spinal cords at various disease stages.
- Three distinct methods were employed: spectrophotometric assay, in situ histochemical enzyme assay, and blue native gel electrophoresis with in-gel histochemistry.
- Comparisons were made between spinal cords expressing mutant SOD1, wild-type SOD1, non-transgenic controls, and different spinal cord regions (ventral horn vs. dorsal horn).
Main Results:
- A significant decrease in mitochondrial ETC enzyme activities was observed in the spinal cord, particularly in the ventral horn, starting at early stages of the disease.
- This reduction in enzyme activity persisted throughout the disease progression.
- No such decrease was found in non-transgenic mice, mice expressing wild-type SOD1, or in the cerebellum and dorsal horn of mutant SOD1 mice.
Conclusions:
- Mitochondrial dysfunction, evidenced by reduced ETC enzyme activity, is a key feature in the ventral horn of the spinal cord during mutant SOD1-induced ALS.
- These findings support the hypothesis that mitochondrial damage is a critical component of the pathogenic pathway leading to motoneuron degeneration in this ALS model.