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Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington's Disease
Tatiana Brustovetsky1, Rajesh Khanna2,3, Nickolay Brustovetsky1,4
1Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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.
Insights
Collapsin response mediator protein 2 (CRMP2) dysfunction causes mitochondrial problems in Huntington's disease (HD). (S)-lacosamide treatment rescued mitochondrial dynamics and protected neurons in HD models.
Area of Science:
- Neuroscience
- Cell Biology
- Neurodegenerative Diseases
Background:
- Mitochondrial dynamics are crucial for synaptic function.
- Huntington's disease (HD) is characterized by mitochondrial fragmentation and reduced motility, but underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the role of collapsin response mediator protein 2 (CRMP2) in regulating mitochondrial dynamics in Huntington's disease (HD).
- To explore the therapeutic potential of (S)-lacosamide ((S)-LCM) in modulating CRMP2 function and mitochondrial health in HD.
Main Methods:
- Investigated CRMP2 interaction with Drp1 and Miro 2 in HD models.
- Assessed CRMP2 phosphorylation levels in postmortem HD brain tissues, patient-derived neurons, and HD mouse models.
- Utilized (S)-lacosamide to treat HD neurons and evaluated effects on mitochondrial dynamics and neuroprotection.
Main Results:
- CRMP2 interacts with Drp1 and Miro 2, proteins regulating mitochondrial dynamics.
- CRMP2 is hyperphosphorylated in HD, leading to diminished interaction with Drp1 and Miro 2, causing mitochondrial fission and reduced motility.
- (S)-lacosamide treatment reduced CRMP2 phosphorylation, restored CRMP2 interaction with Drp1/Miro 2, enhanced mitochondrial motility, and provided neuroprotection in HD models.
Conclusions:
- CRMP2 regulates mitochondrial dynamics in a phosphorylation-dependent manner.
- CRMP2 dysfunction contributes to neuronal pathology in Huntington's disease.
- (S)-lacosamide shows promise for treating HD by restoring mitochondrial function and promoting neuronal survival.
