Inhibition of GSK-3 ameliorates the pathogenesis of Huntington's disease

Rippin, Ido; Bonder, Katherina; Joseph, Shirley Ben; Sarsor, Amar; Vaks, Lilach; Eldar-Finkelman, Hagit

doi:10.1016/j.nbd.2021.105336

Cited by 18 publications

(12 citation statements)

References 90 publications

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“…Moreover, the rapamycin analog CCI-779 promotes clearance of protein aggregates and ameliorates motor deficits in mice expressing mutant HTT (Ravikumar et al 2004 ). A recent study demonstrated that a small molecule inhibitor of serine/threonine kinase GSK-3 can promote clearance of expanded-polyQ HTT aggregates (Rippin et al 2021 ). GSK-3 was initially identified as a central kinase involved in glucose metabolism, which phosphorylates glycogen synthase, insulin receptor 1, phosphoenolpyruvate carboxykinase and glucose 6-phosphatase (Embi et al 1980 ; Liberman and Eldar-Finkelman 2005 ; Lochhead et al 2001 ).…”

Section: Autophagy In Diseasementioning

confidence: 99%

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Protein clearance strategies for disease intervention

Hommen

Bilican

2021

J Neural Transm

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Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.

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Section: Autophagy In Diseasementioning

confidence: 99%

“…Notably, the GSK-3 inhibitor L807mts enhances clearance of aggregates through elevated autophagy in SH-SY5Y cells expressing mutant HTT. Moreover, L807mts improves motor function and coordination in R6/2 mice, a widely used mouse model for HD (Rippin et al 2021 ).…”

Section: Autophagy In Diseasementioning

confidence: 99%

Protein clearance strategies for disease intervention

Hommen

Bilican

2021

J Neural Transm

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“…Some studies found elevated levels of Gsk-3β in the HD cell model [79], whereas others reported decreased Gsk-3β expression and diminished Gsk-3 signaling in HD [80]. Interestingly, the inhibition of Gsk-3α/β ameliorated HD pathogenesis [81], suggesting that Gsk-3α/β remains active in HD and may lead to detrimental consequences.…”

Section: Discussionmentioning

confidence: 99%

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

Brustovetsky

Khanna

Brustovetsky

2021

Cells

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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.

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“…In addition, in HD, neurotoxicity is attenuated by GSK-3β inhibitors. Inhibition of GSK-3β activates mitochondrial lysosomes, leading to timely clearance of toxic aggregates of mutant Huntingtin [ 179 ]. In PD, collapsed response mediator protein 2 (CRMP-2), a downstream signal factor of PI3K/Akt/GSK-3β, regulates the degeneration of axons and dendrites of dopaminergic neurons through microassembly [ 180 ].…”

Section: Exercise Improves Cognitive Function By Improving Brain Meta...mentioning

confidence: 99%

Recent advances on the molecular mechanisms of exercise-induced improvements of cognitive dysfunction

Lü

Wang

et al. 2023

Transl Neurodegener

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Physical exercise is of great significance for maintaining human health. Exercise can provide varying degrees of benefits to cognitive function at all stages of life cycle. Currently, with the aging of the world’s population and increase of life expectancy, cognitive dysfunction has gradually become a disease of high incidence, which is accompanied by neurodegenerative diseases in elderly individuals. Patients often exhibit memory loss, aphasia and weakening of orientation once diagnosed, and are unable to have a normal life. Cognitive dysfunction largely affects the physical and mental health, reduces the quality of life, and causes a great economic burden to the society. At present, most of the interventions are aimed to maintain the current cognitive level and delay deterioration of cognition. In contrast, exercise as a nonpharmacological therapy has great advantages in its nontoxicity, low cost and universal application. The molecular mechanisms underlying the effect of exercise on cognition are complex, and studies have been extensively centered on neural plasticity, the direct target of exercise in the brain. In addition, mitochondrial stability and energy metabolism are essential for brain status. Meanwhile, the organ-brain axis responds to exercise and induces release of cytokines related to cognition. In this review, we summarize the latest evidence on the molecular mechanisms underlying the effects of exercise on cognition, and point out directions for future research.

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Inhibition of GSK-3 ameliorates the pathogenesis of Huntington's disease

Cited by 18 publications

References 90 publications

Protein clearance strategies for disease intervention

Protein clearance strategies for disease intervention

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

Recent advances on the molecular mechanisms of exercise-induced improvements of cognitive dysfunction

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