Browsing by Subject "Fragile X syndrome"

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  • Utami, Kagistia H; Yusof, Nur A B M; Kwa, Jing E; Peteri, Ulla-Kaisa; Castrén, Maija L; Pouladi, Mahmoud A (BioMed Central, 2020)
    Abstract FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS.
  • Utami, Kagistia Hana; Yusof, Nur Amirah Binte Mohammad; Kwa, Jing Eugene; Peteri, Ulla-Kaisa; Castrén, Maija L.; Pouladi, Mahmoud A. (2020)
    FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS.
  • Talvio, Karo; Kanninen, Katja M.; White, Anthony R.; Koistinaho, Jari; Castren, Maija L. (2021)
    Trace elements have important functions in several processes involved in cellular homeostasis and survival. Dysfunctional metal ion homeostasis can make an important impact on cellular defence mechanisms. We assessed the concentrations of 23 trace minerals in different tissues (brain, spleen, heart and liver) of Fmr1 knockout (KO) mice that display the main phenotype of Fragile X syndrome (FXS), an intellectual disability syndrome and the best-known monogenic model of autism spectrum disorder (ASD). Altogether, seven minerals-Cu, Fe, K, Mg, Mn, Na, and P-were above the detection limit with the analysis revealing increased iron content in the heart of Fmr1 KO mice. In addition, levels of iron were higher in the cerebellum of the transgenic mouse when compared to wild type controls. These results implicate a role for dysregulated iron homeostasis in FXS tissues and suggest that defective iron-related mechanisms contribute to increased tissue vulnerability in FXS.
  • Talvio, Karo; Kanninen, Katja; White, Anthony; Koistinaho, Jari; Castrén, Maija (Helsingin yliopisto, 2021)
    Biometalleilla on merkittävä rooli solujen ja kudosten toiminnassa. Ne ovat monen entsyymin toiminnassa elintärkeitä, mutta toisaalta solut pyrkivät pitämään niiden pitoisuudet tarkoissa rajoissa. Metallin yli- tai alimäärä voi joko itsessään vaikeuttaa solujen normaalia toimintaa tai olla merkki epätavallisesta metaboliasta. Fragile X-oireyhtymä on monogeeninen kehitysvammaisuutta aiheuttava perinnällinen sairaus, joka johtuu FMRP-proteiinin puutoksesta. Oireyhtymä on mahdollisesti yleisin periytyvän autismin syy. 23 metallin kudospitoisuudet mitattiin Fragile X-oireyhtymää mallintavan hiirimallin ja kontrollihiirten pikkuaivoista, isoaivokuorelta, maksasta, sydämestä ja pernasta induktiivisesti kytketty plasma -massaspektrometrillä. Seitsemän metallin – Cu, Fe, K, Mg, Mn, Na ja P – pitoisuudet olivat mittausrajan yläpuolella. Hiirimallin sydämen ja pikkuaivojen rautapitoisuudet olivat korkeampia kuin kontrollihiirten vastaavista kudoksista mitatut arvot. Löydösten merkitsevyydet olivat kuitenkin statistisesti raja-arvoisia. PCA-analyysi vahvisti käsitystä muuttuneesta metallihomeostaasista hiirimallin sydämessä, ja toisaalta Fragile X-oireyhtymän aiheuttavan FMRP-proteiinin mutaatiot on aiemmin liitetty ihmisillä pikkuaivojen rautakertymiin. Tutkimus kärsii pienen näytemäärän takia alhaisesta voimasta, mutta rautamuutokset sopivat aiemmin kuvattuun FMRP-proteiiniin liitettyyn inflammaatioon. Tässä tutkimuksessa sekä aiemmissa julkaisuissa kuvattu biometallien epätasapaino edellyttää lisätutkimusta aiheesta, sillä metalleja sisältäviä lisäravinteita kokeillaan usein hoidoksi hermoston kehityshäiriöissä.
  • Utami, Kagistia Hana; Skotte, Nils H.; Colaco, Ana R.; Yusof, Nur Amirah Binte Mohammad; Sim, Bernice; Yeo, Xin Yi; Bae, Han-Gye; Garcia-Miralles, Marta; Radulescu, Carola I.; Chen, Qiyu; Chaldaiopoulou, Georgia; Liany, Herty; Nama, Srikanth; Peteri, Ulla-Kaisa A.; Sampath, Prabha; Castrén, Maija; Jung, Sangyong; Mann, Matthias; Pouladi, Mahmoud (2020)
    BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking. METHODS: Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology. RESULTS: We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells. CONCLUSIONS: Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.
  • Sauna-Aho, Oili; Bjelogrlic-Laakso, Nina; Siren, Auli; Arvio, Maria (2018)
    BackgroundIntellectual disability (ID) and dementia reflect disturbed cortical function during and after developmental age, respectively. Due to the wide heterogeneity of ID population the decline in cognitive and adaptive skills may be different in distinct genetic subgroups. MethodsUsing the British Present Psychiatric State-learning Disabilities assessment (PPS-LD) questionnaire the dementia signs were screened in 62, 22 and 44 individuals (> 35year of age) with Down (DS, OMIM number 190685), Williams (WS, OMIM number, 194050), and Fragile X syndrome (FXS, OMIM number 309550), respectively. The median age of those with FXS (59years) was higher than of those with DS (50years) and WS (53years). ResultsMost study participants with DS (80%) and FXS (89%) were or had been moderately or severely intellectually disabled while most participants with WS (73%) were or had been mildly or moderately disabled at adolescent age. The adolescent (premorbid) level of ID did not correlate with the dementia score. The median scores were 11/27, 1/27, and 0/27 in DS, WS, and FXS subgroups, respectively. Dementia that was confirmed by brain imaging, manifested as Alzheimer disease and as moya-moya disease associated vascular dementia in DS and as vascular dementia in WS. ConclusionsThis survey suggests that the risk of dementia varies depending on the cause of ID and that the severity of ID in adolescence does not predict the development of dementia at a later age. Consequently, the ID and dementia should be understood as separate clinical entities that need to be taken into account in the health management of intellectually disabled people. This is important for the arrangement of appropriate and timely interventions, which can be expected to delay the need for institutionalization.
  • Carroll, Renee; Shaw, Marie; Arvio, Maria; Gardner, Alison; Kumar, Raman; Hodgson, Bree; Heron, Sarah; McKenzie, Fiona; Järvelä, Irma; Gecz, Jozef (2020)
    The major and most well-studied genetic cause of Fragile-X syndrome (FXS) is expansion of a CGG repeat in the 5'-UTR of the FMR1 gene. Routine testing for this expansion is performed globally. Overall, there is a paucity of intragenic variants explaining FXS, a fact which is being addressed by a more systematic application of whole exome (WES) and whole genome (WGS) sequencing, even in the diagnostic setting. Here we report two families comprising probands with a clinical suspicion of FXS and no CGG repeat expansions. Using WES/WGS we identified deleterious variants within the coding region of FMR1 in both families. In a family from Finland we identified a complex indel c.1021-1028delinsTATTGG in exon 11 of FMR1 which gives rise to a frameshift and a premature termination codon (PTC), p.Asn341Tyrfs*7. Follow-up mRNA and protein studies on a cell line from the proband revealed that although the mRNA levels of FMR1 were not altered, Fragile X Mental Retardation 1 Protein (FMRP) was undetectable. Additionally, we identified a variant, c.881-1G > T, affecting the canonical acceptor splice site of exon 10 of FMR1 in an Australian family. Our findings reinforce the importance of intragenic FMR1 variant testing, particularly in cases with clinical features of FXS and no CGG repeat expansions identified.