Early Downregulation of p75 NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington's Disease Mice

Mol Neurobiol. 2019 Feb;56(2):935-953. doi: 10.1007/s12035-018-1126-5. Epub 2018 May 27.

Abstract

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/p75NTR 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/p75NTR 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 p75NTR expression. Genetic normalization of p75NTR 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/p75NTR 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/p75NTR on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75NTR levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75NTR expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75NTR could be promising to prevent motor deficits in HD.

Keywords: BDNF; Huntington’s disease; Motor deficits onset; Striatal pathology; TrkB; p75NTR.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Corpus Striatum / metabolism
  • Corpus Striatum / physiopathology*
  • Dendritic Spines / metabolism
  • Disease Models, Animal
  • Down-Regulation / drug effects*
  • Gene Knock-In Techniques
  • Huntington Disease / genetics
  • Mice, Transgenic
  • Neurons / metabolism
  • Receptor, trkB / metabolism
  • Receptors, Nerve Growth Factor / genetics*

Substances

  • Brain-Derived Neurotrophic Factor
  • Receptors, Nerve Growth Factor
  • TNFRSF16 protein, mouse
  • Receptor, trkB