Increased Actin Polymerization and Stabilization Interferes with Neuronal Function and Survival in the AMPKγ Mutant Loechrig

Cook, Mandy; Bolkan, Bonnie J.; Kretzschmar, Doris

doi:10.1371/journal.pone.0089847

Cited by 11 publications

(9 citation statements)

References 44 publications

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“…In particular, an intact cytoskeleton is crucial to integrate sensory input with motor output, and mutations that disrupt the actin cytoskeleton interfere with learning and memory, locomotion, and neuronal integrity in zebrafish and flies. 62,63 We have previously shown that disruption of Drosophila Hts, the orthologue of human adducin, leads to altered brain development and locomotor abnormalities. 23 These comparatively simple model organisms can thus provide a powerful strategy for investigating how diseaseassociated changes in human proteins interfere with normal function and cause pathology.…”

Section: Developing New Models For Cpmentioning

confidence: 99%

The genetic basis of cerebral palsy

Fahey

MacLennan

Kretzschmar

et al. 2017

Develop Med Child Neuro

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162

123

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Although prematurity and hypoxic-ischaemic injury are well-recognized contributors to the pathogenesis of cerebral palsy (CP), as many as one-third of children with CP may lack traditional risk factors. For many of these children, a genetic basis to their condition is suspected. Recent findings have implicated copy number variants and mutations in single genes in children with CP. Current studies are limited by relatively small patient numbers, the underlying genetic heterogeneity identified, and the paucity of validation studies that have been performed. However, several genes mapping to intersecting pathways controlling neurodevelopment and neuronal connectivity have been identified. Analogous to other neurodevelopmental disorders such as autism and intellectual disability, the genomic architecture of CP is likely to be highly complex. Although we are just beginning to understand genetic contributions to CP, new insights are anticipated to serve as a unique window into the neurobiology of CP and suggest new targets for intervention.

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Section: Developing New Models For Cpmentioning

confidence: 99%

The genetic basis of cerebral palsy

Fahey

MacLennan

Kretzschmar

et al. 2017

Develop Med Child Neuro

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162

123

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“…loe encodes the γ-subunit of AMP-activated protein kinase (AMPK), a key enzyme in regulating energy homeostasis (Kemp et al, 1999 ). AMPK also regulates protein prenylation and loe mutant flies show an increase in Rho prenylation and activity and changes in actin dynamics (Cook et al, 2012 , 2014 ). Interestingly, the Rho pathway has also been connected with modulating Aβ production in vertebrates (Tang and Liou, 2007 ).…”

Section: Appl and Neuronal Survivalmentioning

confidence: 99%

Analysis of Amyloid Precursor Protein Function in Drosophila melanogaster

Cassar

Kretzschmar

2016

Front. Mol. Neurosci.

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The Amyloid precursor protein (APP) has mainly been investigated in connection with its role in Alzheimer’s Disease (AD) due to its cleavage resulting in the production of the Aβ peptides that accumulate in the plaques characteristic for this disease. However, APP is an evolutionary conserved protein that is not only found in humans but also in many other species, including Drosophila, suggesting an important physiological function. Besides Aβ, several other fragments are produced by the cleavage of APP; large secreted fragments derived from the N-terminus and a small intracellular C-terminal fragment. Although these fragments have received much less attention than Aβ, a picture about their function is finally emerging. In contrast to mammals, which express three APP family members, Drosophila expresses only one APP protein called APP-like or APPL. Therefore APPL functions can be studied in flies without the complication that other APP family members may have redundant functions. Flies lacking APPL are viable but show defects in neuronal outgrowth in the central and peripheral nervous system (PNS) in addition to synaptic changes. Furthermore, APPL has been connected with axonal transport functions. In the adult nervous system, APPL, and more specifically its secreted fragments, can protect neurons from degeneration. APPL cleavage also prevents glial death. Lastly, APPL was found to be involved in behavioral deficits and in regulating sleep/activity patterns. This review, will describe the role of APPL in neuronal development and maintenance and briefly touch on its emerging function in circadian rhythms while an accompanying review will focus on its role in learning and memory formation.

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“…ROCK1 and PAK1 act as regulators of cofilin activity by modulating LIM kinase activity. High expression levels of ROCK1 and PAK1 can inhibit cofilin activity, leading to further actin polymerization and F-actin stabilization [ 44 , 45 ]. Our results showed that the expression of ROCK1 and N-WASP induced by PRP/WP enhanced the expression of p-MLC2 and ARP2/3, together with the expression of ROCK1 and PAK1 induced by PRP/WP, leading to cell migration, actin polymerization, and F-actin stabilization.…”

Section: Discussionmentioning

confidence: 99%

Poria cocos Regulates Cell Migration and Actin Filament Aggregation in B35 and C6 Cells by Modulating the RhoA, CDC42, and Rho Signaling Pathways

Lee

Tzeng

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Poria is used as a traditional Chinese herbal medicine with anti-inflammatory, anticancer, and mood-stabilizing properties. Poria contains triterpenoids and polysaccharides, which are reported to regulate the cytoplasmic free calcium associated with the N-methyl-D-aspartate receptor and affect the cell function of neonatal rat nerve cells and hippocampal neurons. Although the modulatory effects of Poria on neuronal function have been widely reported, the molecular mechanism of these effects is unclear. Cell migration ability and the reorganization of actin filaments are important biological functions during neuronal development, and they can be regulated mainly by the Rho signaling pathway. We found that the cell migration ability and actin condensation in B35 cells enhanced by P. cocos (a water solution of P. cocos cum Radix Pini (PRP) or White Poria (WP)) might be caused by increased RhoA and CDC42 activity and increased expression of downstream ROCK1, p-MLC2, N-WASP, and ARP2/3 in B35 cells. Similar modulations of cell migration ability, actin condensation, and Rho signaling pathway were also observed in the C6 glial cell line, except for the PRP-induced regulation of RhoA and CDC42 activities. Ketamine-induced inhibition of cell migration and actin condensation can be restored by P. cocos. In addition, we observed that the increased expression of RhoA and ROCK1 or the decreased expression of CDC42 and N-WASP caused by ketamine in B35 cells could also be restored by P. cocos. The results of this study suggest that the regulatory effects of P. cocos on cell migration and actin filament aggregation are closely related to the regulation of RhoA, CDC42, and Rho signaling pathways in both B35 and C6 cells. PRP and WP have the potential to restore neuronal cell Rho signaling abnormalities involved in some mental diseases.

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Increased Actin Polymerization and Stabilization Interferes with Neuronal Function and Survival in the AMPKγ Mutant Loechrig

Cited by 11 publications

References 44 publications

The genetic basis of cerebral palsy

The genetic basis of cerebral palsy

Analysis of Amyloid Precursor Protein Function in Drosophila melanogaster

Poria cocos Regulates Cell Migration and Actin Filament Aggregation in B35 and C6 Cells by Modulating the RhoA, CDC42, and Rho Signaling Pathways

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