Participation of group I p21-activated kinases in neuroplasticity

Koth, André Peres; Oliveira, B. R. de; Parfitt, Gustavo M.; Buonocore, Juliana de Quadros; Barros, Daniela M.

doi:10.1016/j.jphysparis.2014.08.007

Cited by 23 publications

(15 citation statements)

References 121 publications

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“…4B(iii),C]. Expression of PAK1, the downstream effector for both Rac1 and Cdc42 (Koth et al, 2014; Zhao et al, 2006) and upstream regulator of stathmin1, was reduced in scenario A 1.73-fold ( n =3) but increased in scenario B 1.37-fold ( n =3) [Fig. 4B(iv),C].…”

Section: Resultsmentioning

confidence: 99%

Cellular levels of growth factor receptor bound protein 2 (Grb2) and cytoskeleton stability are correlated in a neurodegenerative scenario

Majumder

Roy

Singh

et al. 2017

Disease Models &Amp; Mechanisms

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Alzheimer's disease (AD) manifests as neuronal loss. On the premise of Grb2 overexpression in AD mouse brain and brain tissues of AD patients, our study primarily focuses on the stability of cytoskeletal proteins in the context of degenerative AD-like conditions. Two predominant molecular features of AD, extracellular accumulation of β-amyloid oligomers and intracellular elevation of amyloid precursor protein intracellular domain levels, have been used to closely inspect the series of signalling events. In their presence, multiple signalling pathways involving ROCK and PAK1 proteins lead to disassembly of the cytoskeleton, and Grb2 partially counterbalances the cytoskeletal loss. Increased Grb2-NOX4 interactions play a preventive role against cytoskeletal disassembly, in turn blocking the activity of nitrogen oxides and decreasing the expression of slingshot homolog 1 (SSH-1) protein, a potent inducer of cytoskeleton disassembly. This study unravels a unique role of Grb2 in protecting the cytoskeletal architecture in AD-like conditions and presents a potential new strategy for controlling neurodegeneration.

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Section: Resultsmentioning

confidence: 99%

Cellular levels of growth factor receptor bound protein 2 (Grb2) and cytoskeleton stability are correlated in a neurodegenerative scenario

Majumder

Roy

Singh

et al. 2017

Disease Models &Amp; Mechanisms

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“…2G and H). Another downstream target of RhoA is p21-activated kinase 1 (PAK1), which, when activated, is neuroprotective and involved in regulating the actin cytoskeleton and neuroplasticity, including LTP consolidation, and increased post-synaptic density (PSD) levels (57–59). R6/2 mice given vehicle had reduced pPAK1 and PSD-95 levels which were normalized by LM11A-31 (Fig.…”

Section: Resultsmentioning

confidence: 99%

A small molecule p75^NTRligand normalizes signalling and reduces Huntington’s disease phenotypes in R6/2 and BACHD mice

et al. 2016

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Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington’s disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75NTR-associated deleterious signalling and decreases survival signalling suggesting that p75NTR could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75NTR ligand, LM11A-31, on HD-related neuropathology in HD mouse models (R6/2, BACHD). LM11A-31 restored striatal AKT and other pro-survival signalling while inhibiting c-Jun kinase (JNK) and other degenerative signalling. Normalizing p75NTR signalling with LM11A-31 was accompanied by reduced Htt aggregates and striatal cholinergic interneuron degeneration as well as extended survival in R6/2 mice. The p75NTR ligand also decreased inflammation, increased striatal and hippocampal dendritic spine density, and improved motor performance and cognition in R6/2 and BACHD mice. These results support small molecule modulation of p75NTR as an effective HD therapeutic strategy. LM11A-31 has successfully completed Phase I safety and pharmacokinetic clinical trials and is therefore a viable candidate for clinical studies in HD.

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“…RhoA-Rho kinase (ROCK) activity 15,16 and Ca 2þ influx 17,18 have been reported to play a role in regulating axonal retraction by rod photoreceptors in both isolated tiger salamander rod cells and detached porcine retinas. This study expands these findings by examining (1) the role of ROCK's downstream effector, LIM kinase (LIMK) [19][20][21] ; (2) the role of p21-activated kinase (Pak), like ROCK, an upstream regulator of LIMK [21][22][23][24] ; and (3) the relationship between Ca 2þ influx and ROCK or LIMK in rod cell injury.…”

mentioning

confidence: 86%

LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

Wang

Townes‐Anderson

2015

Invest. Ophthalmol. Vis. Sci.

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METHODS. Phosphorylated LIMK (p-LIMK), the active form of LIMK, was examined in salamander retina with Western blot and confocal microscopy. Axon length within the first 7 hours and process growth after 3 days of culture were assessed in isolated rod photoreceptors treated with inhibitors of upstream regulators ROCK and p21-activated kinase (Pak) (Y27632 and IPA-3) and a direct LIMK inhibitor (BMS-5). Porcine retinal explants were also treated with BMS-5 and analyzed 24 hours after detachment. Because Ca 2þ influx contributes to axonal retraction, L-type channels were blocked in some experiments with nicardipine. RESULTS.Phosphorylated LIMK is present in rod terminals during retraction and in newly formed processes. Axonal retraction over 7 hours was significantly reduced by inhibition of LIMK or its regulators, ROCK and Pak. Process growth was reduced by LIMK or Pak inhibition especially at the basal (axon-bearing) region of the rod cells. Combining Ca 2þ channel and LIMK inhibition had no additional effect on retraction but did further inhibit sprouting after 3 days. In detached porcine retina, LIMK inhibition reduced rod axonal retraction and improved retinal morphology.CONCLUSIONS. Thus structural remodeling, in the form of either axonal retraction or neuritic growth, requires LIMK activity. LIM kinase inhibition may have therapeutic potential for reducing pathologic rod terminal plasticity after retinal injury.

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Participation of group I p21-activated kinases in neuroplasticity

Cited by 23 publications

References 121 publications

Cellular levels of growth factor receptor bound protein 2 (Grb2) and cytoskeleton stability are correlated in a neurodegenerative scenario

Cellular levels of growth factor receptor bound protein 2 (Grb2) and cytoskeleton stability are correlated in a neurodegenerative scenario

A small molecule p75^NTRligand normalizes signalling and reduces Huntington’s disease phenotypes in R6/2 and BACHD mice

LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

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Participation of group I p21-activated kinases in neuroplasticity

Cited by 23 publications

References 121 publications

Cellular levels of growth factor receptor bound protein 2 (Grb2) and cytoskeleton stability are correlated in a neurodegenerative scenario

Cellular levels of growth factor receptor bound protein 2 (Grb2) and cytoskeleton stability are correlated in a neurodegenerative scenario

A small molecule p75NTRligand normalizes signalling and reduces Huntington’s disease phenotypes in R6/2 and BACHD mice

LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

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A small molecule p75^NTRligand normalizes signalling and reduces Huntington’s disease phenotypes in R6/2 and BACHD mice