Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome

Robin, Gaëlle; López, José R.; Espinal, Glenda; Hulsizer, Susan; Hagerman, Paul J.; Pessah, Isaac N.

doi:10.1093/hmg/ddx148

Cited by 51 publications

(75 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…52 Neuronal networks were exposed to PCBs chronically between 2 and 14 days in vitro (DIV), or acutely at 14 DIV while functional measurements were obtained.…”

Section: Methodsmentioning

confidence: 99%

Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks

Feng

Zheng

Robin

et al. 2017

Environ. Sci. Technol.

Self Cite

View full text Add to dashboard Cite

Nineteen ortho-substituted PCBs are chiral and found enantioselectively enriched in ecosystems. Their differential actions on biological targets are not understood. PCB 95 (2,2′,3,5′,6-pentachlorobiphenyl), a chiral PCB of current environmental relevance, is among the most potent toward modifying ryanodine receptors (RyR) function and Ca2+ signaling. PCB 95 enantiomers are separated and assigned aR- and aS-PCB 95 using three chiral-column HPLC and circular dichroism spectroscopy. Studies of RyR1-enriched microsomes show aR-PCB 95 with >4× greater potency (EC50 = 0.20 ± 0.05 μM), ~ 1.3× higher efficacy (Bmax = 3.74 ± 0.07 μM) in [3H]Ryanodine-binding and >3× greater rates (R = 7.72 ± 0.31 nmol/sec/mg) of Ca2+ efflux compared with aS-PCB 95, whereas racemate has intermediate activity. aR-PCB 95 has modest selectivity for RyR2, and lower potency than racemate toward the RyR isoform mixture in brain membranes. Chronic exposure of hippocampal neuronal networks to nanomolar PCB 95 during a critical developmental period shows divergent influences on synchronous Ca2+ oscillation (SCO): rac-PCB 95 increasing and aR-PCB 95 decreasing SCO frequency at 50 nM, although the latter’s effects are nonmonotonic at higher concentration. aS-PCB95 shows the greatest influence on inhibiting responses to 20 Hz electrical pulse trains. Considering persistence of PCB 95 in the environment, stereoselectivity toward RyRs and developing neuronal networks may clarify health risks associated with enantioisomeric enrichment of PCBs.

show abstract

“…52 Neuronal networks were exposed to PCBs chronically between 2 and 14 days in vitro (DIV), or acutely at 14 DIV while functional measurements were obtained.…”

Section: Methodsmentioning

confidence: 99%

Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks

Feng

Zheng

Robin

et al. 2017

Environ. Sci. Technol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…31,[37][38][39] The FMR1 premutation mouse has also been reported to exhibit aberrant neural migration, 40 and primary neurons derived from FMR1 premutation mice have significantly altered dendritic arborization, 41 increased resting intracellular Ca 2+ concentrations, abnormal patterns of spontaneous Ca 2+ oscillations and altered responses to glutamate in central neurons and astrocytes. 29,30 Several early deficits identified in the premutation mouse model have been corroborated in human iPSC-derived neurons from FMR1 premutation patients. 42 In the present study, we quantified dendritic arborization and social approach behavior in both the T4826I-RYR1 and FMR1 premutation mouse models.…”

mentioning

confidence: 92%

“…A knock‐in mouse that expresses the human FMR1 premutation (170‐200 CGG repeats) exhibits pathology consistent with human carriers or FXTAS patients, including increased FMR1 mRNA, decreased FMRP, ubiquitin‐positive intranuclear inclusions and deficits in spatial learning and memory and motor behavior in adult animals . The FMR1 premutation mouse has also been reported to exhibit aberrant neural migration, and primary neurons derived from FMR1 premutation mice have significantly altered dendritic arborization, increased resting intracellular Ca 2+ concentrations, abnormal patterns of spontaneous Ca 2+ oscillations and altered responses to glutamate in central neurons and astrocytes . Several early deficits identified in the premutation mouse model have been corroborated in human iPSC‐derived neurons from FMR1 premutation patients …”

Section: Introductionmentioning

confidence: 99%

“…A second human mutation known to alter neuronal Ca 2+ signaling is the CGG expansion repeat mutation in fragile X mental retardation gene 1 (FMR1). [28][29][30][31] CGG repeat expansions in the 5 0 non-coding region of FMR1 in the premutation range (55-200 CGG repeats) not only give rise to the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS), but also increase risk for NDDs. [32][33][34][35] Estimated prevalence of the FMR1 premutation is 1:209 in females and 1:430 in males.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Genetic mutations in Ca²⁺ signaling alter dendrite morphology and social approach in juvenile mice

Keil

Sethi

Wilson

et al. 2018

Genes Brain and Behavior

Self Cite

View full text Add to dashboard Cite

Dendritic morphology is a critical determinant of neuronal connectivity, and calcium signaling plays a predominant role in shaping dendrites. Altered dendritic morphology and genetic mutations in calcium signaling are both associated with neurodevelopmental disorders (NDDs). In this study we tested the hypothesis that dendritic arborization and NDD-relevant behavioral phenotypes are altered by human mutations that modulate calcium-dependent signaling pathways implicated in NDDs. The dendritic morphology of pyramidal neurons in CA1 hippocampus and somatosensory cortex was quantified in Golgi-stained brain sections from juvenile mice of both sexes expressing either a human gain-of-function mutation in ryanodine receptor 1 (T4826I-RYR1), a human CGG repeat expansion (170-200 CGG repeats) in the fragile X mental retardation gene 1 (FMR1 premutation), both mutations (double mutation; DM), or wildtype mice. In hippocampal neurons, increased dendritic arborization was observed in male T4826I-RYR1 and, to a lesser extent, male FMR1 premutation neurons. Dendritic morphology of cortical neurons was altered in both sexes of FMR1 premutation and DM animals with the most pronounced differences seen in DM females. Genotype also impaired behavior, as assessed using the three-chambered social approach test. The most striking lack of sociability was observed in DM male and female mice. In conclusion, mutations that alter the fidelity of calcium signaling enhance dendritic arborization in a brain region- and sex-specific manner and impair social behavior in juvenile mice. The phenotypic outcomes of these mutations likely provide a susceptible biological substrate for additional environmental stressors that converge on calcium signaling to determine individual NDD risk.

show abstract

“…How this action contributes to DSB accumulation remains unclear, as ATM activation is required for HR-mediated repair of DSBs. Nonetheless, CDK5 induces neuronal cell death partly via ATM activation [168] (Figure 5) and the connection of CDK5/p25-ATM is a cause of DDR-induced neurodegeneration in a mouse model for fragile-X-associated tremor/ataxia syndrome (FXTAS) [169]. Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis, an event required for 53BP1 recruitment to DSB in G1 phase for NHEJ-mediated repair of DSBs.…”

Section: Role Of Cdk5 Abnormalities In Ad Via Affecting Dna Damagementioning

confidence: 99%

Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

show abstract

Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome

Cited by 51 publications

References 99 publications

Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks

Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks

Genetic mutations in Ca²⁺ signaling alter dendrite morphology and social approach in juvenile mice

Contributions of DNA Damage to Alzheimer’s Disease

Contact Info

Product

Resources

About

Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome

Cited by 51 publications

References 99 publications

Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks

Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks

Genetic mutations in Ca2+ signaling alter dendrite morphology and social approach in juvenile mice

Contributions of DNA Damage to Alzheimer’s Disease

Contact Info

Product

Resources

About

Genetic mutations in Ca²⁺ signaling alter dendrite morphology and social approach in juvenile mice