Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington’s Disease Mice

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/p75 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 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 expression. Genetic normalization of p75 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 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 on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75 levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75 expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75 could be promising to prevent motor deficits in HD.

Synaptic RTP801 contributes to motor-learning dysfunction in Huntington’s disease

“…One of the mechanisms contributing to synaptic impairment in the striatum of HD mouse models is the imbalance between BDNF receptors, TrkB and p75 NTR 42 , 43 . We found that RTP801 silencing increased TrkB levels in both homogenates and synaptosomes of R6/1 mice striatum in comparison to their shCtr-injected R6/1 littermates (Fig.…”

“…However, specifically analyzing protein levels in synaptosomal preparations, we concluded that mhtt leads to a localized aberrant accumulation of RTP801 in synapses that could contribute to plasticity impairment in the pathology. In fact, structural alterations at the morphology and/or spine number in the striatum of the R6/1 55 and the KI 56 have been reported. This observation is also extended to other HD murine models such as N-terminal fragment R6/2 mice 57 , 58 and transgenic full-length htt YAC128 mice 59 .…”

In vivoprogressive degeneration of Huntington’s disease patient-derived neurons reveals human-specific pathological phenotypes

“…Chronic pharmacological treatment with fingolimod (FTY720) was performed as previously described [22]. FTY720 was obtained as a powder (Cayman Chemicals) and dissolved in EtOH 10% in distilled water (vehicle).…”

Synaptic RTP801 Contributes to Motor Learning Dysfunction in Huntington’s Disease

“…Striatal RTP801 silencing induced an increase of AMPA receptor subunit GluA1 at the homogenate fraction in shRTP801-injected R6/1 mice in comparison to shCtr-injected R6/1 mice whereas non-significant tendencies were observed at the synaptic compartment (Fig 7A). One of the mechanisms contributing to synaptic impairment in the striatum of HD mouse models is the imbalance between BDNF receptors, TrkB and p75 NTR 47,48 . We found that RTP801 silencing increased TrkB levels in both homogenates and synaptosomes of R6/1 mice striatum in comparison to their shCtr-injected R6/1 littermates (Figure 7B) whereas p75 NTR was nor modified in any compartment analyzed (Figure 7C).…”

“…However, specifically analyzing protein levels in synaptosomal preparations, we concluded that mhtt leads to a localized aberrant accumulation of RTP801 in synapses that could contribute to plasticity impairment in the pathology. In fact, structural alterations at the morphology and/or spine number in the striatum of the R6/1 59 and the KI 60 have been reported. This observation is also extended to other HD murine models such as N-terminal fragment R6/2 mice 61–63 and transgenic full-length htt YAC128 mice 64 .…”