Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity

Abstract

Huntington disease (HD) is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (HTT). PolyQ length determines disease onset and severity with a longer expansion causing earlier onset. The mechanisms of mutant HTT-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in HD pathogenesis1,2. Here we tested whether mutant HTT impairs the mitochondrial fission/fusion balance and thereby causes neuronal injury. We show that mutant HTT triggers mitochondrial fragmentation in neurons and fibroblasts of HD individuals in vitro and HD mice in vivo before the presence of neurological deficits and HTT aggregates. Interestingly, mutant HTT abnormally interacts with the mitochondrial fission GTPase dynamin-related protein 1 (DRP1) in HD mice and individuals which in turn stimulates its enzymatic activity. Importantly, mutant HTT-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport, and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in HD.

Inhibition of Drp1 provides neuroprotection in vitro and in vivo

“…7 In addition, a very recent study showed that enhanced Drp1 activity caused detrimental mitochondrial fission in Huntington's disease. 27 This study also applied mdiviA, and together with our current findings it is suggested that Drp1 inhibition is a promising approach to prevent mitochondrial fragmentation in different models of delayed neuronal cell death relevant for acute and chronic neurological diseases. In fact, these studies show that Drp1 inhibitors are applicable to neurons in vitro and in vivo, thereby overcoming obstacles of siRNA applications or gene therapy.…”

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

“…Indeed, we showed that insulin or IGF-1 treatment decreased p-Drp1/Drp1 levels. mHtt was previously described to bind Drp1, increasing its activity [62,63]. Increased Drp1 mRNA and protein levels were also found in the cortex and striatum of HD patients [9] in a grade-dependent manner [95].…”

“…mHtt was previously described to bind Drp1, increasing its activity [62,63]. Drp1 is a cytosolic protein that translocates to the outer mitochondrial membrane to promote mitochondrial fragmentation.…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…In contrast to AD, the general consensus in the case of HD is that increased mitochondrial fission is associated with -and perhaps contributes to the pathogenesis of -the disease. According to two independent reports for which post-mortem brain samples from HD patients were analyzed, Drp1 interacts with mutant huntingtin (Song et al, 2011;Shirendeb et al, 2012). Moreover, Drp1 GTPase activity is increased and mitochondria are fragmented in brain samples of HD patients, suggesting that mutant huntingtin also promotes activation of Drp1 (Song et al, 2011;Shirendeb et al, 2012).…”