Inhibition of mitochondrial fragmentation diminishes Huntington’s disease–associated neurodegeneration
Xing Guo, … , Daria Mochly-Rosen, Xin Qi
Xing Guo, … , Daria Mochly-Rosen, Xin Qi
Published November 15, 2013
Citation Information: J Clin Invest. 2013;123(12):5371-5388. https://doi.org/10.1172/JCI70911.
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Research Article Neuroscience

Inhibition of mitochondrial fragmentation diminishes Huntington’s disease–associated neurodegeneration

Abstract

Huntington’s disease (HD) is the result of expression of a mutated Huntingtin protein (mtHtt), and is associated with a variety of cellular dysfunctions including excessive mitochondrial fission. Here, we tested whether inhibition of excessive mitochondrial fission prevents mtHtt-induced pathology. We developed a selective inhibitor (P110-TAT) of the mitochondrial fission protein dynamin-related protein 1 (DRP1). We found that P110-TAT inhibited mtHtt-induced excessive mitochondrial fragmentation, improved mitochondrial function, and increased cell viability in HD cell culture models. P110-TAT treatment of fibroblasts from patients with HD and patients with HD with iPS cell–derived neurons reduced mitochondrial fragmentation and corrected mitochondrial dysfunction. P110-TAT treatment also reduced the extent of neurite shortening and cell death in iPS cell–derived neurons in patients with HD. Moreover, treatment of HD transgenic mice with P110-TAT reduced mitochondrial dysfunction, motor deficits, neuropathology, and mortality. We found that p53, a stress gene involved in HD pathogenesis, binds to DRP1 and mediates DRP1-induced mitochondrial and neuronal damage. Furthermore, P110-TAT treatment suppressed mtHtt-induced association of p53 with mitochondria in multiple HD models. These data indicate that inhibition of DRP1-dependent excessive mitochondrial fission with a P110-TAT–like inhibitor may prevent or slow the progression of HD.

Authors

Xing Guo, Marie-Helene Disatnik, Marie Monbureau, Mehrdad Shamloo, Daria Mochly-Rosen, Xin Qi

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Figure 3

Drp1 bound to p53.

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Drp1 bound to p53. (A) HD striatal cells were treated with P110-TAT or c...
(A) HD striatal cells were treated with P110-TAT or control peptide TAT (1 μM each) for 3 days, and p53 association with the mitochondria was determined by Western blot analysis (loading control, HSP60). Histogram: the data represent mean ± SEM of 3–4 independent experiments. *P < 0.05 vs. wild-type cell treated with TAT; #P < 0.05 vs. HD striatal cells treated with TAT. (B) Top: Total lysates of HD striatal cells were subjected to immunoprecipitation with anti-Drp1 antibody, and immunoprecipitates were analyzed by immunoblotting with anti-p53 and anti-Drp1 antibodies. Data are representative of 3 independent experiments. Bottom: Immunoprecipitates obtained using anti-p53 antibodies were analyzed by immunoblotting using anti-Drp1 and anti-p53 antibodies. Data are representative of 2 independent experiments. (C) GST-Drp1 recombinant protein (500 ng) was incubated with p53 recombinant protein (500 ng). Immunoprecipitates with anti-Drp1 antibodies or anti-p53 antibodies were analyzed by immunoblotting with the indicated antibodies. Data are representative of 2 independent experiments. (D) Mouse wild-type striatal cells were transfected with either control vector or Drp1 plasmid (5 μg and 10 μg, respectively) for 36 hours. In the presence or absence of P110-TAT (1 μM), protein levels of p53 and Drp1 on the mitochondria were analyzed by Western blotting (loading control, VDAC). Quantification of p53 mitochondrial level in cells with Drp1 (10 μg) is presented as mean SEM of 3 independent experiments in the histogram.