Neuronal actin cytoskeleton gain of function in the human brain

Szigeti, Kinga; Ihnatovych, Ivanna; Rosas, Nicolás Matías; Dorn, Ryu; Notari, Emily; Gomez, Eduardo Cortes; He, Muye; Maly, Ivan V.; Prasad, Shreyas; Nimmer, Erik; Heo, Yuna; Fuchsová, Beata; Bennett, David A.; Hofmann, Wilma A.; Pralle, Arnd; Bae, Yongho; Wang, Jianmin

doi:10.1016/j.ebiom.2023.104725

Cited by 7 publications

(18 citation statements)

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“…Mechanistic insights from isogenic induced pluripotent stem cell (iPSC) models identified a direct allele mediated actin cytoskeleton gain of function. Consistent with emerging literature that functional effects of the human specific genes are most frequently observed in the brain, immune system and metabolism we demonstrated gain of function in the neuronal lineage and previously have shown immune gain of function in microglia ( Ihnatovych et al, 2020 ; Szigeti et al, 2023 ). Human specific genes are thought to drive traits that make us human and typically are present in all humans while mutations or absence lead to developmental consequences or disease.…”

Section: Discussionsupporting

confidence: 91%

“…Of note, α7 nAChRs agonists, such as encenicline has been studied in clinical trials in both Alzheimer’s disease and schizophrenia and while animal models showed consistent efficacy all human clinical trials failed identifying a translational gap (NCT01969136 and NCT01969123) ( Prickaerts et al, 2012 ). While CHRFAM7A modifies the α7 nAChR into a hypomorphic ionotropic receptor, at the same time shifts Ca 2+ dynamics in the neuron that activates the actin cytoskeleton ( Szigeti et al, 2023 ). Actin cytoskeleton is a fundamental mechanism in memory formation through stabilizing and maturing synapses resulting in long term potentiation that could account for the observed memory gain of function ( Lamprecht, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…The actin phenotype affects all neuronal substructures, including the cell body, growth cone, and dendritic spine. The reinforced membrane in the presence of CHRFAM7A leads to post-developmental adaptation to changes in stiffness associated with biological and pathological processes ( Szigeti et al, 2023 ). The mechanism suggests that CHRFAM7A infers a more efficient and resilient brain.…”

Section: Introductionmentioning

confidence: 99%

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Human restricted CHRFAM7A gene increases brain efficiency

Jakimovski,

Dorn,

Regno

et al. 2024

Front. Neurosci.

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IntroductionCHRFAM7A, a uniquely human fusion gene, has been associated with neuropsychiatric disorders including Alzheimer’s disease, schizophrenia, anxiety, and attention deficit disorder. Understanding the physiological function of CHRFAM7A in the human brain is the first step to uncovering its role in disease. CHRFAM7A was identified as a potent modulator of intracellular calcium and an upstream regulator of Rac1 leading to actin cytoskeleton reorganization and a switch from filopodia to lamellipodia implicating a more efficient neuronal structure. We performed a neurocognitive-MRI correlation exploratory study on 46 normal human subjects to explore the effect of CHRFAM7A on human brain.MethodsDual locus specific genotyping of CHRFAM7A was performed on genomic DNA to determine copy number (TaqMan assay) and orientation (capillary sequencing) of the CHRFAM7A alleles. As only the direct allele is expressed at the protein level and affects α7 nAChR function, direct allele carriers and non-carriers are compared for neuropsychological and MRI measures. Subjects underwent neuropsychological testing to measure motor (Timed 25-foot walk test, 9-hole peg test), cognitive processing speed (Symbol Digit Modalities Test), Learning and memory (California Verbal Learning Test immediate and delayed recall, Brief Visuospatial Memory Test—Revised immediate and delayed recall) and Beck Depression Inventory—Fast Screen, Fatigue Severity Scale. All subjects underwent MRI scanning on the same 3 T GE scanner using the same protocol. Global and tissue-specific volumes were determined using validated cross-sectional algorithms including FSL’s Structural Image Evaluation, using Normalization, of Atrophy (SIENAX) and FSL’s Integrated Registration and Segmentation Tool (FIRST) on lesion-inpainted images. The cognitive tests were age and years of education-adjusted using analysis of covariance (ANCOVA). Age-adjusted analysis of covariance (ANCOVA) was performed on the MRI data.ResultsCHRFAM7A direct allele carrier and non-carrier groups included 33 and 13 individuals, respectively. Demographic variables (age and years of education) were comparable. CHRFAM7A direct allele carriers demonstrated an upward shift in cognitive performance including cognitive processing speed, learning and memory, reaching statistical significance in visual immediate recall (FDR corrected p = 0.018). The shift in cognitive performance was associated with smaller whole brain volume (uncorrected p = 0.046) and lower connectivity by resting state functional MRI in the visual network (FDR corrected p = 0.027) accentuating the cognitive findings.ConclusionThese data suggest that direct allele carriers harbor a more efficient brain consistent with the cellular biology of actin cytoskeleton and synaptic gain of function. Further larger human studies of cognitive measures correlated with MRI and functional imaging are needed to decipher the impact of CHRFAM7A on brain function.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human restricted CHRFAM7A gene increases brain efficiency

Jakimovski,

Dorn,

Regno

et al. 2024

Front. Neurosci.

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“…While electrophysiological studies have shown that incorporation of CHRFAM7A into the α7 nAChR pentamer results in decreased channel open probability leading to a hypomorphic receptor, 17 , 18 , 49 the effect on Ca 2+ signalling was in need of further characterization. 28 , 29 We systematically assessed the effect of CHRFAM7A on Ca 2+ oscillations using live cell Fluo-4 imaging. Using modelling and Bayesian inference the Ca 2+ signal changes are identified as a shift in utilization of Ca 2+ from extracellular space (hypomorphic α7/CHRFAM7A nAChR) to intracellular (ER) reservoir.…”

Section: Discussionmentioning

confidence: 99%

“… 28 Just recently we have demonstrated that CHRFAM7A modulates intracellular Ca 2+ dynamics in neuronal cells as it shifts time spent in CICR to IICR. 29 …”

Section: Introductionmentioning

confidence: 99%