Group <scp>I PAKs</scp> in myelin formation and repair of the central nervous system: what, when, and how

Wang, Yan; Guo, Fuzheng

doi:10.1111/brv.12815

Cited by 9 publications

(24 citation statements)

References 179 publications

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“…7). Even though we could not exclude that the observed effects of NVS could be related to PAK1 inhibition in neurons and other glial cells (25,26), our results indicate that sustained inhibition of PAK1 activity in OLs promotes myelination ex vivo.…”

Section: Pak1 Inhibition Increases Myelin Membrane Expansion and Myel...mentioning

confidence: 70%

“…We previously showed that PAK3 is highly expressed in OPCs but weakly expressed in OLs and that PAK3 is involved in OPC differentiation (29). Conversely, transcriptome and protein expression analyses have shown that PAK1 is highly expressed in OLs compared to OPCs (26,(30)(31)(32), suggesting that PAK1 may be a relevant candidate for controlling myelin membrane expansion, hence sheath wrapping around axons.…”

Section: Introductionmentioning

confidence: 99%

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PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

Baudouin,

Adès,

Kanté

et al. 2023

Preprint

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In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts the axon, while a drastic shift to actin depolymerization is required to enable the next step of wrapping and expansion of myelin membrane. The molecular mechanisms triggering this switch, essential for proper myelination, have yet to be elucidated. Here, we identify P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. We show that PAK1 accumulates in OLs in a kinase inhibited form, triggering actin disassembly and, consequently, myelin expansion. Remarkably, we identify NF2/Merlin as an endogenous inhibitor of PAK1 by proteomics analysis of its binding partners. We found that Nf2 knockdown in OLs results in PAK1 activation and impairs myelin formation, and that pharmacological inhibition of PAK1 in Nf2-knockdown OLs rescues these defects. Moreover, we demonstrate that modulating PAK1 activity in OLs controls myelin expansion and provide compelling evidence indicating that specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that PAK1-NF2/Merlin duo plays a key role in actin cytoskeleton remodeling in OLs, required for proper myelin formation. These findings have broad mechanistic and therapeutic implications for neurodevelopmental and demyelinating diseases.

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Section: Pak1 Inhibition Increases Myelin Membrane Expansion and Myel...mentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

Baudouin,

Adès,

Kanté

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…PAK3 is mostly expressed in the brain, with a particularly strong expression in the hippocampus. At the cellular level in the brain, PAK1 is found only in neural lineage cells, PAK2 is expressed in every cell types and PAK3 can be found in neurons as well as oligodendrocyte progenitor cells (Figure 5A; Zhang et al, 2014;Maglorius Renkilaraj et al, 2017;Magne et al, 2021;Wang and Guo, 2022). However, some differences were noticed in PAK expression between mouse and human brain (Figure 5A; Civiero and Greggio, 2018;Zhang K. et al, 2022).…”

Section: Pak Expression Patterns and Mutation Pathogenicitymentioning

confidence: 97%

“…Group I PAKs includes PAK1, 2 and 3; group II includes PAK4, 5 and 6 which have not been associated with NDDs yet (Jaffer and Chernoff, 2002;Bokoch, 2003). Several reviews describe the biological functions of PAKs in cell signaling and neuronal pathophysiology (Bokoch, 2003;Kreis and Barnier, 2009;Koth et al, 2014;Kumar and Li, 2016;Civiero and Greggio, 2018;Wang and Guo, 2022;Zhang K. et al, 2022). Functions of group I PAKs are similar in a broad way because of their high sequence identity, their common modes of regulation as well as the substrates they share.…”

Section: Introductionmentioning

confidence: 99%

The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype

Dobrigna

Poëa-Guyon²,

Rousseau³

et al. 2023

Front. Neurosci.

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Although the identification of numerous genes involved in neurodevelopmental disorders (NDDs) has reshaped our understanding of their etiology, there are still major obstacles in the way of developing therapeutic solutions for intellectual disability (ID) and other NDDs. These include extensive clinical and genetic heterogeneity, rarity of recurrent pathogenic variants, and comorbidity with other psychiatric traits. Moreover, a large intragenic mutational landscape is at play in some NDDs, leading to a broad range of clinical symptoms. Such diversity of symptoms is due to the different effects DNA variations have on protein functions and their impacts on downstream biological processes. The type of functional alterations, such as loss or gain of function, and interference with signaling pathways, has yet to be correlated with clinical symptoms for most genes. This review aims at discussing our current understanding of how the molecular changes of group I p21-activated kinases (PAK1, 2 and 3), which are essential actors of brain development and function; contribute to a broad clinical spectrum of NDDs. Identifying differences in PAK structure, regulation and spatio-temporal expression may help understanding the specific functions of each group I PAK. Deciphering how each variation type affects these parameters will help uncover the mechanisms underlying mutation pathogenicity. This is a prerequisite for the development of personalized therapeutic approaches.

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“…Pak1 is an essential Rac1 downstream protein, and research suggests that Rac1/Pak1 signalling pathway plays a signi cant role in healing nervous system injuries [27]. However, the downstream signalling pathway of Rac1/Pak1 in nerve injury repair remains unclear.…”

Section: The Rac1/ Pak1/p38 Signalling Pathway Is Enhanced In Respons...mentioning

confidence: 99%

Post-acute phase Rac1/Pak1/p38/β-catenin signalling activation promotes ischemic recovery and facilitates migration of neural stem cells

Zhang

et al. 2023

Preprint

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Ischemic stroke is one of the world's leading causes of death and disability. During ischemic stroke, neuronal death is caused by inflammation, oxidative stress, apoptosis, and excitatory toxicity. For a long time, there has been a lot of interest in various studies to promote the repair of nerve damage after stroke. However, the mechanisms underlying the complex pathophysiological processes remain to be fully elucidated. Cerebral Ras-related C3 botulinum toxin substrate (Rac) 1 was initially associated with poor prognosis after stroke. However, some recent studies suggest that Rac1 may contribute to the repair process of nerve injury after stroke and promote the recovery of nerve function. However, the current conflicting findings may be related to the timing of Rac1 interventions. Our study found that post-acute Rac1 activation contributes to ischemic recovery. Here, we first investigated the specific role of neuron Rac1 in neuroprotection and recovery of neurological function in the post-acute phase of stroke. We found that intraventricular injection of Rac1 activator beginning one week after MACO significantly improved brain atrophy and neurological function after MACO. Considering the important role of Rac1 in cell migration. In vitro experiments, we found that Rac1 induced NSCs migration after exogenous and endogenous activator stimulation. In vivo, the addition of Rac1 activator in the post-acute phase helped promote the migration of NSCs in SVC to the lesion area and differentiation into mature nerve cells. It is worth noting that Pak1 is an essential downstream protein of Rac1. Our results suggest that while Rac1 activates Pak1, Pak1 can promote the migration and differentiation of neural stem cells through the downstream p38/β-catenin signalling pathway. While promoting neurogenesis, we found that Rac1 promoted angiogenesis and axon remodelling, and enhanced the synaptic plasticity to support the process of nerve repair during the post-acute phase via downstream Pak1/p38/β-catenin signalling. It suggests that Rac1/Pak1/p38/β-catenin signalling may be a potential therapeutic target in the recovery stage of ischemic stroke.

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Group I PAKs in myelin formation and repair of the central nervous system: what, when, and how

Cited by 9 publications

References 179 publications

PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype

Post-acute phase Rac1/Pak1/p38/β-catenin signalling activation promotes ischemic recovery and facilitates migration of neural stem cells

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