PMID- 29804232 OWN - NLM STAT- MEDLINE DCOM- 20190711 LR - 20231213 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 56 IP - 2 DP - 2019 Feb TI - Early Downregulation of p75(NTR) by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington's Disease Mice. PG - 935-953 LID - 10.1007/s12035-018-1126-5 [doi] AB - Deficits in striatal brain-derived neurotrophic factor (BDNF) delivery and/or BDNF/tropomyosin receptor kinase B (TrkB) signaling may contribute to neurotrophic support reduction and selective early degeneration of striatal medium spiny neurons in Huntington's disease (HD). Furthermore, we and others have demonstrated that TrkB/p75(NTR) imbalance in vitro increases the vulnerability of striatal neurons to excitotoxic insults and induces corticostriatal synaptic alterations. We have now expanded these studies by analyzing the consequences of BDNF/TrkB/p75(NTR) imbalance in the onset of motor behavior and striatal neuropathology in HD mice. Our findings demonstrate for the first time that the onset of motor coordination abnormalities, in a full-length knock-in HD mouse model (KI), correlates with the reduction of BDNF and TrkB levels, along with an increase in p75(NTR) expression. Genetic normalization of p75(NTR) expression in KI mutant mice delayed the onset of motor deficits and striatal neuropathology, as shown by restored levels of striatal-enriched proteins and dendritic spine density and reduced huntingtin aggregation. We found that the BDNF/TrkB/p75(NTR) imbalance led to abnormal BDNF signaling, manifested as a diminished activation of TrkB-phospholipase C-gamma pathway but upregulation of c-Jun kinase pathway. Moreover, we confirmed the contribution of the proper balance of BDNF/TrkB/p75(NTR) on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75(NTR) levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75(NTR) expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75(NTR) could be promising to prevent motor deficits in HD. FAU - Suelves, Nuria AU - Suelves N AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Miguez, Andres AU - Miguez A AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Lopez-Benito, Saray AU - Lopez-Benito S AD - Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y Leon (INCyL), University of Salamanca, Salamanca, Spain. AD - Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. FAU - Barriga, Gerardo Garcia-Diaz AU - Barriga GG AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Giralt, Albert AU - Giralt A AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Alvarez-Periel, Elena AU - Alvarez-Periel E AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Arevalo, Juan Carlos AU - Arevalo JC AD - Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y Leon (INCyL), University of Salamanca, Salamanca, Spain. AD - Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. FAU - Alberch, Jordi AU - Alberch J AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Gines, Silvia AU - Gines S AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciencies, Universitat de Barcelona, Barcelona, Spain. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. FAU - Brito, Veronica AU - Brito V AD - Departament de Biomedicina, Facultat de Medicina, Institut de Neurosciencies, Universitat de Barcelona, Barcelona, Spain. veronica.brito@ub.edu. AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. veronica.brito@ub.edu. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. veronica.brito@ub.edu. LA - eng GR - SAF-2014-57160R/Ministerio de Ciencia e Innovacion/ GR - SAF2015-67474-R/Ministerio de Ciencia e Innovacion/ GR - A-3468/CHDI Foundation/ PT - Journal Article DEP - 20180527 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Receptors, Nerve Growth Factor) RN - 0 (Ngfr protein, mouse) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism/*pharmacology MH - Corpus Striatum/metabolism/*physiopathology MH - Dendritic Spines/metabolism MH - Disease Models, Animal MH - Down-Regulation/*drug effects MH - Gene Knock-In Techniques MH - Huntington Disease/genetics MH - Mice, Transgenic MH - Neurons/metabolism MH - Receptor, trkB/metabolism MH - Receptors, Nerve Growth Factor/*genetics OTO - NOTNLM OT - BDNF OT - Huntington's disease OT - Motor deficits onset OT - Striatal pathology OT - TrkB OT - p75NTR EDAT- 2018/05/29 06:00 MHDA- 2019/07/12 06:00 CRDT- 2018/05/28 06:00 PHST- 2018/03/13 00:00 [received] PHST- 2018/05/11 00:00 [accepted] PHST- 2018/05/29 06:00 [pubmed] PHST- 2019/07/12 06:00 [medline] PHST- 2018/05/28 06:00 [entrez] AID - 10.1007/s12035-018-1126-5 [pii] AID - 10.1007/s12035-018-1126-5 [doi] PST - ppublish SO - Mol Neurobiol. 2019 Feb;56(2):935-953. doi: 10.1007/s12035-018-1126-5. Epub 2018 May 27.