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

Tatiana Brustovetsky,Rajesh Khanna,Nickolay Brustovetsky

doi:10.3390/cells10113172

Abstract

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.

Highlights

Huntington’s disease (HD) is a hereditary neurodegenerative disorder linked to a single mutation in exon 1 of the Htt gene, encoding protein huntingtin (HTT) [1]
We found that collapsin response mediator protein 2 (CRMP2) is hyperphosphorylated in HD
In HD, mitochondria per se may not be damaged by mutant huntingtin (mHTT), and there is a significant body of evidence strongly arguing against the primary etiological factor of mitochondrial bioenergetic deficiency as a contributor to HD pathogenesis [11,12,13,14,15,16,17,18,19]

Summary

Introduction

Huntington’s disease (HD) is a hereditary neurodegenerative disorder linked to a single mutation in exon 1 of the Htt gene, encoding protein huntingtin (HTT) [1] This mutation results in an increased number of CAG repeats (>35) in the Htt gene and subsequently to the elongation of polyglutamine stretch in HTT [2]. In recent years, the role of mitochondrial dysfunction in HD pathogenesis was questioned, and compelling data indicating the lack of overt bioenergetic deficits in brain mitochondria in pre-symptomatic and early symptomatic mouse models were provided [11,12,13,14,15,16,17,18,19].

Methods

Results

Conclusion