PMID- 29783994 OWN - NLM STAT- MEDLINE DCOM- 20181109 LR - 20181114 IS - 1750-1326 (Electronic) IS - 1750-1326 (Linking) VI - 13 IP - 1 DP - 2018 May 21 TI - Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse. PG - 25 LID - 10.1186/s13024-018-0259-3 [doi] LID - 25 AB - BACKGROUND: Huntington Disease (HD) is an incurable autosomal dominant neurodegenerative disorder driven by an expansion repeat giving rise to the mutant huntingtin protein (mHtt), which is known to disrupt a multitude of transcriptional pathways. Pridopidine, a small molecule in development for treatment of HD, has been shown to improve motor symptoms in HD patients. In HD animal models, pridopidine exerts neuroprotective effects and improves behavioral and motor functions. Pridopidine binds primarily to the sigma-1 receptor, (IC50 ~ 100 nM), which mediates its neuroprotective properties, such as rescue of spine density and aberrant calcium signaling in HD neuronal cultures. Pridopidine enhances brain-derived neurotrophic factor (BDNF) secretion, which is blocked by putative sigma-1 receptor antagonist NE-100, and was shown to upregulate transcription of genes in the BDNF, glucocorticoid receptor (GR), and dopamine D1 receptor (D1R) pathways in the rat striatum. The impact of different doses of pridopidine on gene expression and transcript splicing in HD across relevant brain regions was explored, utilizing the YAC128 HD mouse model, which carries the entire human mHtt gene containing 128 CAG repeats. METHODS: RNAseq was analyzed from striatum, cortex, and hippocampus of wild-type and YAC128 mice treated with vehicle, 10 mg/kg or 30 mg/kg pridopidine from the presymptomatic stage (1.5 months of age) until 11.5 months of age in which mice exhibit progressive disease phenotypes. RESULTS: The most pronounced transcriptional effect of pridopidine at both doses was observed in the striatum with minimal effects in other regions. In addition, for the first time pridopidine was found to have a dose-dependent impact on alternative exon and junction usage, a regulatory mechanism known to be impaired in HD. In the striatum of YAC128 HD mice, pridopidine treatment initiation prior to symptomatic manifestation rescues the impaired expression of the BDNF, GR, D1R and cAMP pathways. CONCLUSIONS: Pridopidine has broad effects on restoring transcriptomic disturbances in the striatum, particularly involving synaptic transmission and activating neuroprotective pathways that are disturbed in HD. Benefits of treatment initiation at early disease stages track with trends observed in the clinic. FAU - Kusko, Rebecca AU - Kusko R AD - Immuneering Corporation, Cambridge, MA, 02142, USA. FAU - Dreymann, Jennifer AU - Dreymann J AD - Research and Development, Teva Pharmaceutical Industries Ltd, Netanya, Israel. FAU - Ross, Jermaine AU - Ross J AD - Immuneering Corporation, Cambridge, MA, 02142, USA. FAU - Cha, Yoonjeong AU - Cha Y AD - Immuneering Corporation, Cambridge, MA, 02142, USA. FAU - Escalante-Chong, Renan AU - Escalante-Chong R AD - Immuneering Corporation, Cambridge, MA, 02142, USA. FAU - Garcia-Miralles, Marta AU - Garcia-Miralles M AD - Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore, 138648, Singapore. FAU - Tan, Liang Juin AU - Tan LJ AD - Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore, 138648, Singapore. FAU - Burczynski, Michael E AU - Burczynski ME AD - Research and Development, Teva Pharmaceutical Industries Ltd, Netanya, Israel. FAU - Zeskind, Ben AU - Zeskind B AD - Immuneering Corporation, Cambridge, MA, 02142, USA. FAU - Laifenfeld, Daphna AU - Laifenfeld D AD - Research and Development, Teva Pharmaceutical Industries Ltd, Netanya, Israel. FAU - Pouladi, Mahmoud AU - Pouladi M AD - Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore, 138648, Singapore. AD - Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. FAU - Geva, Michal AU - Geva M AD - Research and Development, Teva Pharmaceutical Industries Ltd, Netanya, Israel. FAU - Grossman, Iris AU - Grossman I AD - Research and Development, Teva Pharmaceutical Industries Ltd, Netanya, Israel. FAU - Hayden, Michael R AU - Hayden MR AD - Research and Development, Teva Pharmaceutical Industries Ltd, Netanya, Israel. Michael.Hayden@teva.co.il. AD - Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore, 138648, Singapore. Michael.Hayden@teva.co.il. AD - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada. Michael.Hayden@teva.co.il. AD - Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. Michael.Hayden@teva.co.il. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180521 PL - England TA - Mol Neurodegener JT - Molecular neurodegeneration JID - 101266600 RN - 0 (Neuroprotective Agents) RN - 0 (Piperidines) RN - HD4TW8S2VK (pridopidine) SB - IM MH - Animals MH - Brain/drug effects MH - Gene Expression/*drug effects MH - Gene Expression Profiling MH - Humans MH - *Huntington Disease MH - Mice MH - Mice, Transgenic MH - Neuroprotection/*drug effects MH - Neuroprotective Agents/*pharmacology MH - Piperidines/*pharmacology MH - Synaptic Transmission/drug effects PMC - PMC5963017 OTO - NOTNLM OT - Huntington disease OT - Movement disorders OT - Neurodegeneration COIS- AUTHORS' INFORMATION: Information for all the co-authors is listed in the title page. ETHICS APPROVAL: All mouse experiments were performed with the approval of and in accordance with the Institutional Animal Care and Use Committee at the Biomedical Sciences Institute at the Agency for Science, Technology and Research. COMPETING INTERESTS: RK, JR, YC, REC, BZ are employees of Immuneering Corporation. JD, MEB, DL, MG, IG, and MRH are employees of Teva Pharmaceutical. Teva Pharmaceuticals played no role in the treatment or testing of animals, or the collection, or analysis of the results. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/05/23 06:00 MHDA- 2018/11/10 06:00 PMCR- 2018/05/21 CRDT- 2018/05/23 06:00 PHST- 2018/04/09 00:00 [received] PHST- 2018/05/13 00:00 [accepted] PHST- 2018/05/23 06:00 [entrez] PHST- 2018/05/23 06:00 [pubmed] PHST- 2018/11/10 06:00 [medline] PHST- 2018/05/21 00:00 [pmc-release] AID - 10.1186/s13024-018-0259-3 [pii] AID - 259 [pii] AID - 10.1186/s13024-018-0259-3 [doi] PST - epublish SO - Mol Neurodegener. 2018 May 21;13(1):25. doi: 10.1186/s13024-018-0259-3.