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Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease.

TitleSelective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease.
Publication TypeJournal Article
Year of Publication2015
AuthorsMa Q, Yang J, Li T, Milner TA, Hempstead BL
JournalNeurobiol Dis
Volume82
Pagination466-477
Date Published2015 Oct
ISSN1095-953X
KeywordsAdaptor Proteins, Vesicular Transport, Aging, Animals, Brain-Derived Neurotrophic Factor, Corpus Striatum, Disease Models, Animal, Gene Knock-In Techniques, Hippocampus, Huntington Disease, Male, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath, Oligodendroglia, Protein Isoforms, Receptor, trkB, Receptors, Nerve Growth Factor, Sensorimotor Cortex
Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by massive loss of medium spiny neurons in the striatum. However, the mechanisms by which mutant huntingtin leads to this selective neuronal death remain incompletely understood. Brain-derived neurotrophic factor (BDNF) has been shown to be neuroprotective on HD striatal neurons both in vitro and in vivo. ProBDNF, the precursor of mature BDNF (mBDNF), also can be secreted but promotes apoptosis of neurons expressing p75(NTR) and sortilin receptors. Although a reduction of total striatal BDNF protein has been reported in HD patients and mouse models, it remains unclear whether conversion of proBDNF to mBDNF is altered in HD, and whether the proBDNF receptors, p75(NTR) and sortilin are dysregulated, leading to impaired striatal neuron survival. To test these hypotheses, we generated bdnf-HA knock-in (KI) mice on the zQ175 HD background to accurately quantitate the levels of both proBDNF and mBDNF in the HD striatum. In aged zQ175 HD mice, we observed a significant loss of mBDNF and decreased TrkB activation, but no increase of proBDNF or p75(NTR) levels either in the sensorimotor cortex or the striatum. However, immunoreactivities of p75(NTR) and sortilin receptor are both increased in immature striatal oligodendrocytes, which associate with significant myelin defects in the HD striatum. Taken together, the present study indicates that diminished mature BDNF trophic signaling through the TrkB receptor, rather than an induction in proBDNF, is a main contributing factor to the vulnerability of striatal neurons in the zQ175 HD mouse model.

DOI10.1016/j.nbd.2015.08.008
Alternate JournalNeurobiol. Dis.
PubMed ID26282324
PubMed Central IDPMC4819334
Grant ListHL96571 / HL / NHLBI NIH HHS / United States
DA08259 / DA / NIDA NIH HHS / United States
P01 HD023315 / HD / NICHD NIH HHS / United States
R01 NS064114 / NS / NINDS NIH HHS / United States
R01 DA008259 / DA / NIDA NIH HHS / United States
R01 HL098351 / HL / NHLBI NIH HHS / United States
R01 NS030687 / NS / NINDS NIH HHS / United States
NS064114 / NS / NINDS NIH HHS / United States
HL098351 / HL / NHLBI NIH HHS / United States
P01 HL096571 / HL / NHLBI NIH HHS / United States
NS030687 / NS / NINDS NIH HHS / United States