Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS

Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670, USA.
Neuron (Impact Factor: 15.05). 08/2010; 67(4):575-87. DOI: 10.1016/j.neuron.2010.07.019
Source: PubMed


Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. This interaction is found on isolated spinal cord mitochondria and can be reconstituted with purified components in vitro. ADP passage through the outer membrane is diminished in spinal mitochondria from mutant SOD1-expressing ALS rats. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of individual channels when reconstituted in a lipid bilayer. Reduction of VDAC1 activity with targeted gene disruption is shown to diminish survival by accelerating onset of fatal paralysis in mice expressing the ALS-causing mutation SOD1(G37R). Taken together, our results establish a direct link between misfolded mutant SOD1 and mitochondrial dysfunction in this form of inherited ALS.

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    • "In SOD1 G93A mice, a mouse model of familial ALS, mutant SOD1 protein accumulates in mitochondria early during disease (Deng et al., 2006; Higgins et al., 2002; Luo et al., 2013). This build up of mutant protein is suggested to impair mitochondrial function (Israelson et al., 2010; Pasinelli et al., 2004; Song et al., 2013). In line with these findings, mitochondria had a metabolic switch from oxidative phosphorylation to glycolysis in transgenic SOD1 G93A mice, NSC34 cells (motor neuron-like cell line) and fibroblasts transfected with mutant SOD1 compared with controls (Allen et al., 2013; Mattiazzi et al., 2002; Richardson et al., 2013). "
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    ABSTRACT: Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a master regulator of energy balance. As energy imbalance is documented as a key pathologic feature of amyotrophic lateral sclerosis (ALS), we investigated AMPK as a pharmacologic target in SOD1G93A mice. We noted a strong activation of AMPK in lumbar spinal cords of SOD1G93A mice. Pharmacologic activation of AMPK has shown protective effects in neuronal "preconditioning" models. We tested the hypothesis that "preconditioning" with a small molecule activator of AMPK, latrepirdine, exerts beneficial effects on disease progression. SOD1G93A mice (n = 24 animals per group; sex and litter matched) were treated with latrepirdine (1 μg/kg, intraperitoneal) or vehicle from postnatal day 70 to 120. Treatment with latrepirdine increased AMPK activity in primary mouse motor neuron cultures and in SOD1G93A lumbar spinal cords. Mice "preconditioned" with latrepirdine showed a delayed symptom onset and a significant increase in life span (p < 0.01). Our study suggests that "preconditioning" with latrepirdine may represent a possible therapeutic strategy for individuals harboring ALS-associated gene mutations who are at risk for developing ALS.
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    • "These early changes are often followed by a substantial increase in mitochondrial vacuolization at the time of symptom onset (Kong and Xu, 1998; Bendotti et al., 2001). Other studies have shown that mutant SOD G37R binds directly to a voltage-dependent anion channel in the outer mitochondrial membrane and that this interaction inhibits channel conductance (Israelson et al., 2010). Moreover, deletion of this channel results in decreased lifespan of the G37R mouse. "
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    • "An unbalanced turnover, recycling/elimination of the entire mitochondria through selective autophagy is indeed considered an early event involved in the pathogenesis of Charcot–Marie–Tooth (CMT) disease, PD, AD, HD (Lin and Beal, 2006; Wang et al., 2009; Batlevi and La Spada, 2011; Imai and Lu, 2011; Karbowski and Neutzner, 2012; Nunnari and Suomalainen, 2012; Sheng and Cai, 2012; Chaturvedi and Beal, 2013; Itoh et al., 2013), amyotrophic lateral sclerosis (ALS; Cozzolino and Carrì, 2012), cerebral ischemic models (Calo et al., 2013), schizophrenia, and depression (Deheshi et al., 2013). To this regard, it is worth mentioning that patogenetic and/or misfolded/aggregated proteins such as mutated superoxide dismutase in ALS (Israelson et al., 2010), mutant huntingtin in HD (Rockabrand et al., 2007), β-amyloid (Aβ), and tau in AD (Caspersen et al., 2005; Manczak et al., 2006; Hansson Petersen et al., 2008; Amadoro et al., 2010, 2012; Du et al., 2012; Schmitt et al., 2012), mutant α-synuclein in PD (Devi et al., 2008) in vivo accumulate on mitochondria causing their functional decline which, in turn, may affect their mitophagic "
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