title: The p75 neurotrophin receptor augments survival signaling in the striatum of pre-symptomatic Q175(WT/HD) mice.
abstract: 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 neurotrophin receptor (p75), are improperly regulated in the 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 Hdh(+/Q175);p75(-/-) mice to determine if p75 represents a promising therapeutic target. In Hdh(+/Q175);p75(+/+) mice, we observed enhanced survival signaling as evidenced by an increase in phosphorylation and activation of Akt and the p65 subunit of NFκB in the striatum at 5 months of age and an increase in XIAP expression compared to Hdh(+/+);p75(+/+) mice; this increase was lost in Hdh(+/Q175);p75(-/-) mice. Hdh(+/Q175);p75(-/-) mice also showed a decrease in Bcl-XL expression by immunoblotting compared to Hdh(+/Q175);p75(+/+) and Hdh(+/+);p75(+/+) littermates. Consistent with diminished survival signaling, DARPP-32 expression decreased both by immunoblotting and by immunohistochemistry in Hdh(+/Q175);p75(-/-) mice compared to Hdh(+/+);p75(+/+), Hdh(+/Q175);p75(+/+), and Hdh(+/+);p75(-/-) littermates. Additionally, striatal volume declined to a greater extent in Hdh(+/Q175);p75(-/-) when compared to Hdh(+/Q175);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 Hdh(+/Q175) mice.
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Neuroscience Graduate Program, University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Wehner
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Milen
authors.affiliation: Neuroscience Graduate Program, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Albin
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Neuroscience Graduate Program, University of Michigan School of Medicine, Ann Arbor, MI, USA. Electronic address: pierchal@umich.edu.
authors.forename: B A
authors.initials: BA
authors.lastname: Pierchala
mesh_terms: D017668:Age of Onset; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005260:Female; D055879:Gene Knock-In Techniques; D000071058:Huntingtin Protein; D006816:Huntington Disease; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; C107521:Birc4 protein, mouse; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D051034:Inhibitor of Apoptosis Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C497929:Ppp1r1b protein, mouse; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D051996:Transcription Factor RelA; D051020:bcl-X Protein; D051057:Proto-Oncogene Proteins c-akt
keywords: BDNF; Huntington’s; Q175; p75