Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the IT-15 gene; however, it remains unknown how the mutation leads to selective neurodegeneration. Several lines of evidence suggest impaired mitochondrial function as a component of the neurodegenerative process in HD. We assessed energy metabolism in the skeletal muscle of 15 HD patients and 12 asymptomatic mutation carriers in vivo using 31P magnetic resonance spectroscopy. Phosphocreatine recovery after exercise is a direct measure of ATP synthesis and was slowed significantly in HD patients and mutation carriers in comparison to age- and gender-matched healthy controls. We found that oxidative function is impaired to a similar extent in manifest HD patients and asymptomatic mutation carriers. Our findings suggest that mitochondrial dysfunction is an early and persistent component of the pathophysiology of HD.

Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

“…17 The inclusion bodies we observed in ex vivo myotubes resemble htt-immunoreactive granular deposits, recently detected in human post-mortem HD muscles. 9 Our findings provide evidence favoring increased apoptotic death in HD myoblasts (Figure 2), with reduced viability under stressful conditions (Figure 3b-f). As myoblasts are essential, in vivo, for normal growth, repair, and maintenance of adult skeletal muscle bulk, 18 an increased rate of cell death associated with impaired myotube formation may contribute to the progressive weight loss observed in patients with HD.…”

“…8 Furthermore, immunohistochemical studies detected the formation of htt aggregates in human skeletal muscle. 9 Abnormal features have also been confirmed in an HD transgenic mouse model R6/2, where similar degenerative changes involved both brain and muscle fibers. Precisely, analysis of R6/2 peripheral tissues identified htt inclusions and atrophy in muscle fibers, whereas htt inclusions were absent from other peripheral tissues including skin and adipose tissue.…”

“…*Po0.05, **Po0.01 versus control myoblasts changes reported by morphological analyses of human HD skeletal muscle. 8 Previous reports have described altered mitochondrial oxidative metabolism in brain and peripheral tissues of HD subjects [6][7][8][9]19 and increased mitochondrial depolarization after stress conditions in both fibroblasts and lymphoblasts from HD subjects. 20,21 In our cell model, we observed mitochondrial DC m dissipation and cytochrome c release even under normal growth conditions.…”

Bioenergetic dysfunction in Huntington's disease human cybrids

“…Nevertheless, unchanged phosphocreatine was observed after inhibition of mitochondrial ATP generation with oligomycin. Previous studies showed low levels of phosphocreatine/ inorganic phosphate ratio in muscle of HD patients compared to control subjects (Lodi et al, 2000) and a delayed recovery of phosphocreatine levels in HD patients in response to exercise (Saft et al, 2005). Peripherally, a significant decrease in phosphocreatine/ inorganic phosphate ratio was found in resting muscle (Koroshetz et al, 1997) of HD patients.…”

Neuroprotection for Huntington’s Disease: Ready, Set, Slow

“…29 Progressive atrophy of the striatum and cerebral cortex has been well documented to occur in the premanifest prodrome period, indicating that the neurodegenerative process is ongoing. 21,28,30 Subtle cognitive, motor, psychiatric, [31][32][33] and metabolic abnormalities 34,35 are detectable in premanifest HD, and biochemical alterations are beginning to be detected in blood. 24,36 It is unknown whether the HD prodrome represents a stable condition until some decompensation causes manifest HD to emerge, or whether it is a continuum in which clinically silent neurodegeneration gradually accumulates sufficiently to cause unequivocal symptoms.…”