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A21 Muscle Phenotype in Human HD
  1. M Orth
  1. Department of Neurology, Ulm University, Ulm, Germany

Abstract

Background Huntington’s disease (HD) primarily affects the brain. However, the HTT CAG repeat expansion mutation is also expressed in peripheral tissues. In skeletal muscle, like brain a post-mitotic tissue, multiple mitochondrial DNA deletions as well as variable deficits in complex I of the mitochondrial respiratory chain (MRC), abnormal calcium handling, and reduced expression of PGC-1α have been described. In addition, myoblast cell cultures from pre-manifest and manifest HD subjects showed impaired cell differentiation and HTT inclusions similar to those in brain.

Aims To highlight the similarities, and differences, between neurones and muscle. To investigate histological phenotype, mitochondrial biogenesis, MRC assembly and MRC function in quadriceps muscle from patients with HD.

Material and Methods We investigated tissue from near to motor onset pre-manifest HD (n = 20), early onset HD patients (n = 20) and sex and age matched healthy controls (n = 20), as part of the Multi-Tissue Molecular signatures in HD project (MTM-HD).

Results/outcome Report on the histopathology; in addition, I will show data on the expression of PGC-1α and one of its downstream targets, the mitochondrial transcription factor TFAM. Since TFAM regulates mitochondrial DNA transcription we determined the amount of mitochondrial DNA copies. Mitochondrial DNA encodes subunits of the respiratory chain complexes I, III and IV. We therefore assessed the assembly and the levels of the MRC complexes and measured their activities.

Conclusions a) the muscle phenotype itself with potential repercussions for the pathophysiology of the brain; b) how could muscle tissue be used in treatment trials.

KeyWords
  • mitochondrial biogenesis
  • mitochondrial DNA
  • mtDNA copy number
  • mitochondrial respiratory chain assembly
  • PGC-1α
  • TFAM

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