| Huntington's disease (HD) is a dominantly-inherited neurodegenerative disorder characterized by a constellation of motor, cognitive, and psychiatric features. Striatal medium spiny neurons, one of the most affected populations, are dependent on brain-derived neurotrophic factor (BDNF) anterogradely transported from the cortex for proper function and survival. Recent studies suggest both receptors for BDNF, TrkB and p75, are improperly regulated in striata of HD patients and mouse models of HD. While BDNF-TrkB signaling almost exclusively promotes survival and metabolic function, p75 signaling is able to induce survival or apoptosis depending on the available ligand and associated co-receptor. We investigated the role of p75 in the Q175 knock-in mouse model of HD by examining the levels and activation of downstream signaling molecules, and subsequently examining Q175WT/HD;p75 -/- mice to determine if p75 represents a promising therapeutic target. In Q175WT/HD;p75-/- mice, we observed enhanced survival signaling as evidenced by an increase in phosphorylation and activation of Akt and the p65 subunit of NFkB in the striatum at 5 months of age and an increase in XIAP expression compared to Q175 WT/WT;p75+/+ mice; this increase was lost in Q175WT/HD;p75-/- mice. Q175WT/HD;p75-/- mice also showed a decrease in Bcl-XL expression by immunoblotting compared to Q175 WT/HD;p75+/+ and Q175WT/WT ;p75+/+ littermates. Consistent with diminished survival signaling, DARPP-32 expression decreased both by immunoblotting and by immunohistochemistry in Q175WT/HD;p75 -/- mice compared to Q175WT/WT;p75 +/+, Q175WT/HD;p75+/+, and Q175WT/WT;p75-/- littermates. Additionally, striatal volume declined to a greater extent in Q175 WT/HD;p75-/- when compared to Q175 WT/HD;p75+/+ littermates at 12 months, indicating a more aggressive onset of degeneration. These data suggest that p75 signaling plays an early role in augmenting pro-survival signaling in the striatum and that disruption of p75 signaling at a pre-symptomatic age may exacerbate pathologic changes in Q175WT/HD mice. |
