Figure 8. P110-TAT reduces neuropathology in HD R6/2 mice.

(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.