Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease

Mitochondrial morphology and motility (mitochondrial dynamics) play a major role in the proper functioning of distant synapses. In Huntington’s disease (HD), mitochondria become fragmented and less motile, but the mechanisms leading to these changes are not clear. Here, we found that collapsin respo...

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Autores principales:	Tatiana Brustovetsky, Rajesh Khanna, Nickolay Brustovetsky
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Huntington’s disease neuron mitochondria morphology motility CRMP2 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/52726ca640a44c678b12cd5b3e6876b1
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spelling	oai:doaj.org-article:52726ca640a44c678b12cd5b3e6876b12021-11-25T17:12:20ZInvolvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease10.3390/cells101131722073-4409https://doaj.org/article/52726ca640a44c678b12cd5b3e6876b12021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3172https://doaj.org/toc/2073-4409Mitochondrial morphology and motility (mitochondrial dynamics) play a major role in the proper functioning of distant synapses. In Huntington’s disease (HD), mitochondria become fragmented and less motile, but the mechanisms leading to these changes are not clear. Here, we found that collapsin response mediator protein 2 (CRMP2) interacted with Drp1 and Miro 2, proteins involved in regulating mitochondrial dynamics. CRMP2 interaction with these proteins inversely correlated with CRMP2 phosphorylation. CRMP2 was hyperphosphorylated in postmortem brain tissues of HD patients, in human neurons derived from induced pluripotent stem cells from HD patients, and in cultured striatal neurons from HD mouse model YAC128. At the same time, CRMP2 interaction with Drp1 and Miro 2 was diminished in HD neurons. The CRMP2 hyperphosphorylation and dissociation from Drp1 and Miro 2 correlated with increased fission and suppressed motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Thr 509/514 and Ser 522 and rescued CRMP2’s interaction with Drp1 and Miro 2. This was accompanied by reduced mitochondrial fission and enhanced mitochondrial motility. Additionally, (S)-LCM exerted a neuroprotective effect in YAC128 cultured neurons. Thus, our data suggest that CRMP2 may regulate mitochondrial dynamics in a phosphorylation-dependent manner and modulate neuronal survival in HD.Tatiana BrustovetskyRajesh KhannaNickolay BrustovetskyMDPI AGarticleHuntington’s diseaseneuronmitochondriamorphologymotilityCRMP2Biology (General)QH301-705.5ENCells, Vol 10, Iss 3172, p 3172 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Huntington’s disease neuron mitochondria morphology motility CRMP2 Biology (General) QH301-705.5
spellingShingle	Huntington’s disease neuron mitochondria morphology motility CRMP2 Biology (General) QH301-705.5 Tatiana Brustovetsky Rajesh Khanna Nickolay Brustovetsky Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease
description	Mitochondrial morphology and motility (mitochondrial dynamics) play a major role in the proper functioning of distant synapses. In Huntington’s disease (HD), mitochondria become fragmented and less motile, but the mechanisms leading to these changes are not clear. Here, we found that collapsin response mediator protein 2 (CRMP2) interacted with Drp1 and Miro 2, proteins involved in regulating mitochondrial dynamics. CRMP2 interaction with these proteins inversely correlated with CRMP2 phosphorylation. CRMP2 was hyperphosphorylated in postmortem brain tissues of HD patients, in human neurons derived from induced pluripotent stem cells from HD patients, and in cultured striatal neurons from HD mouse model YAC128. At the same time, CRMP2 interaction with Drp1 and Miro 2 was diminished in HD neurons. The CRMP2 hyperphosphorylation and dissociation from Drp1 and Miro 2 correlated with increased fission and suppressed motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Thr 509/514 and Ser 522 and rescued CRMP2’s interaction with Drp1 and Miro 2. This was accompanied by reduced mitochondrial fission and enhanced mitochondrial motility. Additionally, (S)-LCM exerted a neuroprotective effect in YAC128 cultured neurons. Thus, our data suggest that CRMP2 may regulate mitochondrial dynamics in a phosphorylation-dependent manner and modulate neuronal survival in HD.
format	article
author	Tatiana Brustovetsky Rajesh Khanna Nickolay Brustovetsky
author_facet	Tatiana Brustovetsky Rajesh Khanna Nickolay Brustovetsky
author_sort	Tatiana Brustovetsky
title	Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease
title_short	Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease
title_full	Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease
title_fullStr	Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease
title_full_unstemmed	Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease
title_sort	involvement of crmp2 in regulation of mitochondrial morphology and motility in huntington’s disease
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/52726ca640a44c678b12cd5b3e6876b1
work_keys_str_mv	AT tatianabrustovetsky involvementofcrmp2inregulationofmitochondrialmorphologyandmotilityinhuntingtonsdisease AT rajeshkhanna involvementofcrmp2inregulationofmitochondrialmorphologyandmotilityinhuntingtonsdisease AT nickolaybrustovetsky involvementofcrmp2inregulationofmitochondrialmorphologyandmotilityinhuntingtonsdisease
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Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease

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