Abstract
Huntington’s disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.
Highlights
Huntington’s disease (HD) is a devastating and fatal, autosomal dominant neurodegenerative disease whose etiology is simple but poorly understood
We used additional assay formats to determine tropomyosin-receptor kinase B (TrkB) receptor activation status, which included: a) direct measurement of signal transduction phosphorylation events by western blot, b) Meso Scale Discovery assay for quantitative measurement of phospho/total AKT in the human neuroblastoma cell line, SH-SY5Y, which expresses endogenous TrkB upon retinoic acid differentiation, and c) an HD relevant primary neuronal mHTT-induced cell death assay, where Brain-derived neurotrophic factor (BDNF) is neuroprotective for striatal neurons
A significant body of work indicates that the BDNF-TrkB axis is an attractive target to develop novel therapeutics for HD
Summary
Huntington’s disease (HD) is a devastating and fatal, autosomal dominant neurodegenerative disease whose etiology is simple but poorly understood. The CAG codon encodes for the expression of the amino acid glutamine (Gln or Q); expansion of the polyglutamine (polyQ) chain on the N-terminus of the huntingtin (HTT) protein beyond 39 repeats affords a mutant form (mHTT) which leads to the onset of disease with complete penetrance. This expanded polyQ mutant form of HTT misfolds and aggregates, which occurs concomitantly with disease progression [8,9]. Current treatments are symptomatic and include neuroleptics, antipsychotics and antidepressants, with motor symptoms being treated with the only approved HD drug, tetrabenazine, a vesicular monoamine transporter (V-MAT) inhibitor
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