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 8

P110-TAT reduces neuropathology in HD R6/2 mice.

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P110-TAT reduces neuropathology in HD R6/2 mice. (A and C) Coronal secti...
(A and C) Coronal sections of mouse brains were stained with anti-DARPP-32 Abs (A) or anti-EM48 Abs (C). Photomicrographs of DARPP-32 or EM-48 immunostaining were obtained of the dorsolateral striatum of TAT-treated or P110-TAT-treated mice. Bottom panels show magnification of boxed areas. (B) Quantification of DARPP-32 immunodensity (see Methods) by an observer blinded to the experimental conditions. (D) Quantification of the number (left) and average size (right) of Htt aggregates recognized by anti-EM48 by an observer blinded to the experimental conditions. Data represent 3 mice. (E) Transmission electron microscopy images of striatum samples from 13-week-old wild-type and R6/2 mice. Arrows indicate mitochondria with a loss of cristae. Original magnification, ×6,000. Top and middle panels show different section orientations; bottom panels show magnification of boxed areas. Representative images are shown. (F) Quantification of ratio between cristae surface area and mitochondrial surface area. At least 40 mitochondria were analyzed in each group by an observer blinded to the experimental conditions. (G) Drp1 and p53 interact in the cytoplasm and translocate together to the mitochondria in a Drp1-dependent manner in the presence of mtHtt. P110-TAT, a selective peptide inhibitor of Drp1, blocked Drp1 association with the mitochondria, which in turn inhibited Drp1/p53 accumulation on the mitochondria and suppressed the subsequent p53-induced mitochondrial and neuronal damage incurred under conditions relevant to HD. *P < 0.05 vs. wild-type mice treated with TAT; #P < 0.05 vs. R6/2 mice treated with TAT.