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Collapsin Response Mediator Protein 2 (CRMP2) Modulates Mitochondrial Oxidative Metabolism in Knock-In AD Mouse Model
Tatiana Brustovetsky1, Rajesh Khanna2,3, Nickolay Brustovetsky1,4
1Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Abstract:
We explored how the phosphorylation state of collapsin response mediator protein 2 (CRMP2) influences mitochondrial functions in cultured cortical neurons and cortical synaptic mitochondria isolated from APP-SAA KI mice, a knock-in APP mouse model of Alzheimer's disease (AD). CRMP2 phosphorylation was increased at Thr 509/514 and Ser 522 in brain cortical lysates and cultured neurons from AD mice. The basal and maximal respiration of AD neurons were decreased. Mitochondria were hyperpolarized and superoxide anion production was increased in neurons from AD mice. In isolated synaptic AD mitochondria, ADP-stimulated and DNP-stimulated respiration were decreased, whereas ADP-induced mitochondrial depolarization was reduced and prolonged. We found that CRMP2 binds to the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. The increased CRMP2 phosphorylation in AD mice correlated with CRMP2 dissociation from the ANT and decreased ANT activity in AD mitochondria. On the other hand, recombinant CRMP2 (rCRMP2), added to the ANT-reconstituted proteoliposomes, increased ANT activity. A small molecule (S)-lacosamide ((S)-LCM), which binds to CRMP2 and suppresses CRMP2 phosphorylation by Cdk5 and GSK-3β, prevented CRMP2 hyperphosphorylation, rescued CRMP2 binding to the ANT, improved ANT activity, and restored the mitochondrial membrane potential and respiratory responses to ADP and 2,4-dinitrophenol. Thus, our study highlights an important role for CRMP2 in regulating the mitochondrial oxidative metabolism in AD by modulating the ANT activity in a phosphorylation-dependent manner.
Insights
Collapsin response mediator protein 2 (CRMP2) phosphorylation disrupts mitochondrial function in Alzheimer's disease (AD) by affecting adenine nucleotide translocase (ANT) activity. (S)-lacosamide restored mitochondrial function by reducing CRMP2 phosphorylation.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Alzheimer's Disease Research
Background:
- Alzheimer's disease (AD) is characterized by progressive neurodegeneration.
- Mitochondrial dysfunction is a key pathological feature in AD.
- Collapsin response mediator protein 2 (CRMP2) phosphorylation is implicated in neuronal processes.
Purpose of the Study:
- To investigate the impact of CRMP2 phosphorylation state on mitochondrial function in an Alzheimer's disease mouse model.
- To elucidate the mechanism by which CRMP2 influences mitochondrial oxidative metabolism.
- To evaluate the therapeutic potential of (S)-lacosamide in restoring mitochondrial function via CRMP2 modulation.
Main Methods:
- Utilized cultured cortical neurons and isolated synaptic mitochondria from APP-SAA KI mice (AD model).
- Assessed mitochondrial respiration, membrane potential, and superoxide production.
- Investigated CRMP2 binding to adenine nucleotide translocase (ANT) using biochemical assays.
- Examined the effects of recombinant CRMP2 and (S)-lacosamide on ANT activity and mitochondrial function.
Main Results:
- CRMP2 phosphorylation was elevated in AD mice, correlating with decreased neuronal respiration and increased mitochondrial superoxide production.
- Increased CRMP2 phosphorylation led to CRMP2 dissociation from ANT, reducing ANT activity.
- Recombinant CRMP2 enhanced ANT activity, while (S)-lacosamide treatment prevented CRMP2 hyperphosphorylation, restored CRMP2-ANT binding, improved ANT activity, and normalized mitochondrial function.
Conclusions:
- CRMP2 phosphorylation plays a critical role in regulating mitochondrial oxidative metabolism in Alzheimer's disease.
- Modulation of CRMP2 phosphorylation by (S)-lacosamide offers a potential therapeutic strategy for AD by restoring mitochondrial function through ANT activity.
- Targeting the CRMP2-ANT interaction presents a novel avenue for AD treatment.
