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Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice
Marta Garcia-Miralles, … , Michael R. Hayden, Mahmoud A. Pouladi
Marta Garcia-Miralles, … , Michael R. Hayden, Mahmoud A. Pouladi
Published December 7, 2017
Citation Information: JCI Insight. 2017;2(23):e95665. https://doi.org/10.1172/jci.insight.95665.
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Research Article Neuroscience Therapeutics

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

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Abstract

Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, animals received 0, 10, or 30 mg/kg pridopidine for a period of 10.5 months. In the late treatment cohort, animals were treated for 8 weeks with 0 mg/kg or an escalating dose of pridopidine (10 to 30 mg/kg over 3 weeks). Early treatment improved motor coordination and reduced anxiety- and depressive-like phenotypes in YAC128 mice, but it did not rescue striatal and corpus callosum atrophy. Late treatment, conversely, only improved depressive-like symptoms. RNA-seq analysis revealed that early pridopidine treatment reversed striatal transcriptional deficits, upregulating disease-specific genes that are known to be downregulated during HD, a finding that is experimentally confirmed herein. This suggests that pridopidine exerts beneficial effects at the transcriptional level. Taken together, our findings support continued clinical development of pridopidine for HD, particularly in the early stages of disease, and provide valuable insight into the potential therapeutic mode of action of pridopidine.

Authors

Marta Garcia-Miralles, Michal Geva, Jing Ying Tan, Nur Amirah Binte Mohammad Yusof, Yoonjeong Cha, Rebecca Kusko, Liang Juin Tan, Xiaohong Xu, Iris Grossman, Aric Orbach, Michael R. Hayden, Mahmoud A. Pouladi

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Figure 4

Effect of early pridopidine treatment on neuropathology in YAC128 HD mice at 12 months of age.

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Effect of early pridopidine treatment on neuropathology in YAC128 HD mic...
(A and B) Analysis of HD-related pathology by structural MRI revealed decreased striatal (A) and CC (B) volume in vehicle-treated YAC28 HD mice. No effect on striatal and CC volume were observed following pridopidine treatment. (C and D) Vehicle-treated YAC128 HD mice showed decreased forebrain weight (C) and decreased striatal volume (stereological assessment) (D). No effect of pridopidine treatment was observed in both measures in YAC128 HD mice. (E) Investigation of striatal neuronal loss showed no differences in estimated number of striatal counts between genotypes or between treatment groups. (F) A trend toward a decrease in DARPP32 OD was observed in vehicle-treated YAC128 mice, whereas high-dose pridopidine showed a trend toward an increment. No effect was observed with low-dose pridopidine. (G–K) Transcriptome profiling revealed a reduction of reads in striatal-enriched genes, such as Ppp1r1b (Darpp32) (G), Cnr1 (H), Drd1 (I), Drd2 (J), and Penk (K) in vehicle-treated YAC128 mice at 11 months of age. High-dose pridopidine reversed Drd1 (H), Drd2 (J), and Penk (K) transcriptional deficits, whereas the low dose reversed Ppp1r1b (Darpp32) (G), Drd1 (I) and Drd2 (J). Pridopidine had no effect on Cnr1 reads at either dose (H). Box-and-whisker plots show median (line within box), 25th and 75th percentile (bounds of box), and minimum and maximum values (bars). (A, B, and D–F) n = 7–10 WT-vehicle, n = 6–9 YAC128-vehicle, n = 8–9 YAC128-pridopidine (10 mg/kg), n = 8–11 YAC128-pridopidine (30 mg/kg). ***P < 0.001 by 1-way ANOVA with Fisher’s LSD post-hoc analysis. (C) n = 12 WT-vehicle, n = 18 YAC128-vehicle, n = 19 YAC128-pridopidine (10 mg/kg), n = 17 YAC128-pridopidine (30 mg/kg). ***P < 0.001 by 1-way ANOVA with Fisher’s LSD post-hoc analysis. (G–K) n = 6 WT-vehicle, n = 9 YAC128-vehicle, n = 8 YAC128-pridopidine (10 mg/kg), n = 8 YAC128-pridopidine (30 mg/kg). ***P < 0.001 by limma; #P < 0.05, ##P < 0.01, ###P < 0.001 (compared with vehicle-treated YAC128 HD mice) by limma. CC, corpus callosum; Vol, volume; Veh, vehicle; Pri, pridopidine; Low, 10 mg/kg; High, 30 mg/kg; Ppp1r1b, protein phosphatase 1 regulatory subunit 1B; Cnr1, cannabinoid receptor 1; Drd1, dopamine receptor 1; Drd2, dopamine receptor 2; Penk, proenkephalin.

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