Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease.
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.
Graduate Program of Neuroscience, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Qian
Q
Ma
Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Jianmin
J
Yang
Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Thomas
T
Li
Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Teresa A
TA
Milner
Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address: blhempst@med.cornell.edu.
Barbara L
BL
Hempstead
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D009836:Oligodendroglia / Q000378:metabolism / Q000648:ultrastructure; D020033:Protein Isoforms; D020813:Receptor, trkB / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D066191:Sensorimotor Cortex / Q000378:metabolism*; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D020033:Protein Isoforms; D020813:Receptor, trkB; D017475:Receptors, Nerve Growth Factor; D000099183:Sortilin; C517634:Ngfr protein, mouse
Cortex; Huntington's disease; Mature BDNF; Myelin; Oligodendrocyte; ProBDNF; Sortilin; Striatum; p75(NTR); zQ175 mice