A Gain of Function of the Huntington’s Disease and Amyotrophic Lateral Sclerosis-Associated Genetic Mutations May Be a Loss of Bioenergetics

  • M. F. Beal
Conference paper
Part of the Research and Perspectives in Alzheimer’s Disease book series (ALZHEIMER)


There is accumulating evidence for bioenergetic defects that may be involved in the pathogenesis of neurodegenerative diseases. In Huntington’s disease (HD), the genetic defect is a CAG repeat expansion in a gene that encodes the protein huntingtin, whose function is unknown. Several lines of evidence have demonstrated that the HD mutation is associated with abnormalities in bioenergetics, both in lymphoblasts of patients as well as in postmortem brain material and in living patients, as assessed by MRI spectroscopy. Furthermore, recent studies in a transgenic mouse model of HD have shown that there are marked decreases in N-acetylaspartate and increases in glutamine consistent with a bioenergetic defect. In familial amyotrophic lateral sclerosis (FALS), there are point mutations in the enzyme copper/zinc superoxide dismutase (SOD1). Transgenic mice that overexpress SOD1 with FALS-associated mutations show prominent vacuolization of mitochondria, a finding that correlates with cell loss in the spinal cord as well as impaired motor function. Both the HD and FALS mutations appear to result in a gain of function. A consequence of this gain of function may be a deficit in bioenergetics. If this is the case, then several therapeutic strategies may be useful. We found that oral administration of the mitochondrial cofactor coenzyme Q10 or of the creatine kinase substrate creatine can significantly increase survival in transgenic mouse models of both ALS and HD. These may, therefore, be novel approaches for the treatment of these illnesses.


Amyotrophic Lateral Sclerosis Sporadic Amyotrophic Lateral Sclerosis Familial Amyotrophic Lateral Sclerosis Adenine Nucleotide Transporter Creatine Administration 
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  • M. F. Beal

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