Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines

Abstract

Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding huntingtin protein (Htt), but the mechanisms by which this mutant protein causes neurodegeneration remain unknown. Here we show that lymphoblast mitochondria from patients with HD have a lower membrane potential and depolarize at lower calcium loads than do mitochondria from controls. We found a similar defect in brain mitochondria from transgenic mice expressing full-length mutant huntingtin, and this defect preceded the onset of pathological or behavioral abnormalities by months. By electron microscopy, we identified N-terminal mutant huntingtin on neuronal mitochondrial membranes, and by incubating normal mitochondria with a fusion protein containing an abnormally long polyglutamine repeat, we reproduced the mitochondrial calcium defect seen in human patients and transgenic animals. Thus, mitochondrial calcium abnormalities occur early in HD pathogenesis and may be a direct effect of mutant huntingtin on the organelle.

Bioenergetic dysfunction in Huntington's disease human cybrids

“…Lymphoblasts derived from HD patients also showed increased stress-induced apoptotic cell death associated with caspase-3 activation, abnormal calcium homeostasis and mitochondrial dysfunction (Bezprozvanny and Hayden, 2004;Panov et al, 2002;Sawa et al, 1999). Previously, we demonstrated that HD human peripheral blood cells, particularly B lymphocytes, are endowed with increased expression of Bax and decreased mitochondrial membrane potential (Almeida et al, 2008), further suggesting that an adverse effect of mutant huntingtin is not limited to neurons.…”

“…Mutant huntingtin may cause mitochondrial dysfunction by either perturbing transcription of nuclear-encoded mitochondrial proteins or by directly interacting with the organelle, thus evoking defects in mitochondrial dynamics, organelle trafficking and fission and fusion, which, in turn, may result in bioenergetic failure in HD (Bossy-Wetzel et al, 2008). In fact, mutant huntingtin was previously shown to interact with neuronal mitochondria of YAC72 transgenic mice (Panov et al, 2002), suggesting that mitochondrial calcium abnormalities associated with HD pathogenesis may be due to a direct effect of mutant huntingtin on the organelle (Choo et al, 2004;Panov et al, 2002).…”

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

“…It was also demonstrated that oral treatment with rosiglitazone induced mitochondrial biogenesis in mouse brain (25). Therefore, in this study, we explored the possibility of using PPAR␥ activation to ameliorate mutant huntingtin-induced mitochondrial dysfunction (5,6,26). Our results indicate that there are significant defects in the PPAR␥ signaling pathway in mutant huntingtin-expressing cells in comparison with cells that express wild-type huntingtin protein.…”

“…PPAR␥ activation has been proposed to increase mitochondrial biogenesis in vivo (25), and treatment with PPAR␥ agonists has been proven successful in ameliorating neurodegenerative damage in ischemia and ALS (16,37). Therefore, our aim was to determine if PPAR␥ activation could ameliorate the mutant huntingtin-induced mitochondrial dysfunction observed by our group (6,28) and others (5,26,38). Under basal conditions, mutant cells present with low levels of PPAR␥ expression, in comparison with wild-type cells (Fig.…”

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

“…Peptides with pathological polyglutamine repeats (>35-40 residues) insert into artificial membranes (Hirakura et al 2000a ;Monoi et al 2000 ;Kagan et al 2001) and also affect mitochondrial Ca 2+ homeostasis (Panov et al 2002). Furthermore a polyglutamine (Gln40) peptide produced homogeneous pore-like protofibrillar structures in vitro, while a shortened peptide did not (Monoi et al 2000).…”