Title:Neurotrophin Receptor Signaling as a Therapeutic Target for Huntington's Disease
VOLUME: 16 ISSUE: 3
Author(s):Danielle A. Simmons, Frank M. Longo and Stephen M. Massa*
Affiliation:Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, Department of Neurology, San Francisco VAMC and UCSF, MS127, San Francisco, CA 94121
Abstract:Effective non-genetic disease modifying treatments for Huntington’s disease (HD) will necessarily
target multiple diverse neurodegenerative processes triggered by mutant huntingtin. Neurotrophin
receptors are well-positioned for this task as they regulate signaling pathways that largely overlap
with signaling networks contributing to HD-related synaptic dysfunction, glial activation, excitotoxicity,
and other degenerative processes. This review will discuss the contributions of disrupted neurotrophin
receptor-related signaling to primary HD neuropathologies, and prospects for harnessing this signaling
to develop therapeutics to counteract HD degenerative mechanisms. Application of the native protein
ligands has been challenging pharmacologically, but progress has been made with the advent of small
molecule compounds that can selectively bind to and activate specific Trk receptors or p75NTR to promote
trophic and/or inhibit degenerative signaling in cell populations preferentially affected in HD.
