{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T20:49:51Z","timestamp":1780778991649,"version":"3.54.1"},"reference-count":116,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T00:00:00Z","timestamp":1696291200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JHD"],"published-print":{"date-parts":[[2023,10,3]]},"abstract":"<jats:p>Background: Loss of neurotrophic support in the striatum, particularly reduced brain-derived neurotrophic factor (BDNF) levels, contributes importantly to Huntington\u2019s disease (HD) pathogenesis. Another neurotrophin (NT), NT-3, is reduced in the cortex of HD patients; however, its role in HD is unknown. BDNF and NT-3 bind with high affinity to the tropomyosin receptor-kinases (Trk) B and TrkC, respectively. Targeting TrkB\/TrkC may be an effective HD therapeutic strategy, as multiple links exist between their signaling pathways and HD degenerative mechanisms. We developed a small molecule ligand, LM22B-10, that activates TrkB and TrkC to promote cell survival. Objective: This study aimed to determine if upregulating TrkB\/TrkC signaling with LM22B-10 would alleviate the HD phenotype in R6\/2 and Q140 mice. Methods: LM22B-10 was delivered by concomitant intranasal-intraperitoneal routes to R6\/2 and Q140 mice and then motor performance and striatal pathology were evaluated. Results: NT-3 levels, TrkB\/TrkC phosphorylation, and AKT signaling were reduced in the R6\/2 striatum; LM22B-10 counteracted these deficits. LM22B-10 also reduced intranuclear huntingtin aggregates, dendritic spine loss, microglial activation, and degeneration of dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP-32) and parvalbumin-containing neurons in the R6\/2 and\/or Q140 striatum. Moreover, both HD mouse models showed improved motor performance after LM22B-10 treatment. Conclusions: These results reveal an NT-3\/TrkC signaling deficiency in the striatum of R6\/2 mice, support the idea that targeting TrkB\/TrkC alleviates HD-related neurodegeneration and motor dysfunction, and suggest a novel, disease-modifying, multi-target strategy for treating HD.<\/jats:p>","DOI":"10.3233\/jhd-230589","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T10:52:03Z","timestamp":1692960723000},"page":"215-239","source":"Crossref","is-referenced-by-count":10,"title":["Pharmacological Co-Activation of TrkB and TrkC Receptor Signaling Ameliorates Striatal Neuropathology and Motor Deficits in Mouse Models of Huntington\u2019s Disease"],"prefix":"10.1177","volume":"12","author":[{"given":"Danielle A.","family":"Simmons","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia P.","family":"Belichenko","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank M.","family":"Longo","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"issue":"6","key":"10.3233\/JHD-230589_ref1","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","article-title":"Neuropathological classification of Huntington\u2019s disease","volume":"44","author":"Vonsattel","year":"1985","journal-title":"J Neuropathol Exp Neurol"},{"key":"10.3233\/JHD-230589_ref2","doi-asserted-by":"crossref","unstructured":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. 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