Browsing by Subject "DYSREGULATION"

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  • 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.
  • Felszeghy, Szabolcs; Viiri, Johanna; Paterno, Jussi J.; Hyttinen, Juha M. T.; Koskela, Ali; Chen, Mei; Leinonen, Henri; Tanila, Heikki; Kivinen, Niko; Koistinen, Arto; Toropainen, Elisa; Amadio, Marialaura; Smedowski, Adrian; Reinisalo, Mika; Winiarczyk, Mateusz; Mackiewicz, Jerzy; Mutikainen, Maija; Ruotsalainen, Anna-Kaisa; Kettunen, Mikko; Jokivarsi, Kimmo; Sinha, Debasish; Kinnunen, Kati; Petrovski, Goran; Blasiak, Janusz; Bjorkoy, Geir; Koskelainen, Ari; Skottman, Heli; Urtti, Arto; Salminen, Antero; Kannan, Ram; Ferrington, Deborah A.; Xu, Heping; Levonen, Anna-Liisa; Tavi, Pasi; Kauppinen, Anu; Kaarniranta, Kai (2019)
    Age-related macular degeneration (AMD) is a multi-factorial disease that is the leading cause of irreversible and severe vision loss in the developed countries. It has been suggested that the pathogenesis of dry AMD involves impaired protein degradation in retinal pigment epithelial cells (RPE). RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, DNA and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the two major proteolytic systems in eukaryotic cells. NRF-2 (nuclear factor-erythroid 2-related factor-2) and PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are master transcription factors in the regulation of cellular detoxification. We investigated the role of NRF-2 and PGC-1 alpha in the regulation of RPE cell structure and function by using global double knockout (dKO) mice. The NRF-2/PGC-1 alpha dKO mice exhibited significant age-dependent RPE degeneration, accumulation of the oxidative stress marker, 4-HNE (4-hydroxynonenal), the endoplasmic reticulum stress markers GRP78 (glucose-regulated protein 78) and ATF4 (activating transcription factor 4), and damaged mitochondria. Moreover, levels of protein ubiquitination and autophagy markers p62/SQSTM1 (sequestosome 1), Beclin-1 and LC3B (microtubule associated protein 1 light chain 3 beta) were significantly increased together with the Iba-1 (ionized calcium binding adaptor molecule 1) mononuclear phagocyte marker and an enlargement of RPE size. These histopathological changes of RPE were accompanied by photoreceptor dysmorphology and vision loss as revealed by electroretinography. Consequently, these novel findings suggest that the NRF-2/PGC-1 alpha dKO mouse is a valuable model for investigating the role of proteasomal and autophagy clearance in the RPE and in the development of dry AMD.
  • Chouliaras, Leonidas; Pishva, Ehsan; Haapakoski, Rita; Zsoldos, Eniko; Mahmood, Abda; Filippini, Nicola; Burrage, Joe; Mill, Jonathan; Kivimäki, Mika; Lunnon, Katie; Ebmeier, Klaus P. (2018)
    Aim: The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. Methods: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. Results: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to beta-amyloid processing and glutamatergic signaling. Conclusion: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging.
  • Saukkonen, Kapo; Hagstrom, Jaana; Mustonen, Harri; Juuti, Anne; Nordling, Stig; Kallio, Pauliina; Alitalo, Kari; Seppanen, Hanna; Haglund, Caj (2016)
    Background: The Wnt/beta-catenin pathway has a key role in regulating cellular processes and its aberrant signaling can lead to cancer development. The role of beta-catenin expression in pancreatic ductal adenocarcinoma is somewhat controversial. Transcription factor PROX1 is a target of Wnt/beta-catenin signaling and it is involved in carcinogenesis through alterations in its expression. The actions can be either oncogenic or tumor suppressive depending on the tissue. The aim of this study was to investigate PROX1 and beta-catenin expression in pancreatic ductal adenocarcinoma (PDAC). Methods: Expression of PROX1 and beta-catenin were evaluated in 156 patients by immunohistochemistry of tissue microarrays. Associations between tumor marker expression and clinicopathological parameters were assessed by the Fischer's exact-test or the linear-by-linear association test. The Kaplan-Meier method and log-rank test were used for survival analysis. Uni- and multivariate survival analyses were carried out by the Cox regression proportional hazard model. Results: High PROX1 expression was seen in 74 (48 %) tumors, and high beta-catenin expression in 100 (65 %). High beta-catenin expression was associated with lower tumor grade (p = 0.025). High PROX1 and beta-catenin expression associated significantly with lower risk of death from PDAC in multivariate analysis (HR = 0.63; 95 % CI 0.42-0.95, p = 0.026; and HR = 0.54; 95 % CI 0.35-0.82, p = 0.004; respectively). The combined high expression of PROX1 and beta-catenin also predicted lower risk of death from PDAC (HR = 0.46; 95 % CI 0.28-0.76, p = 0.002). Conclusion: In conclusion, high PROX1 and beta-catenin expression were independent factors for better prognosis in pancreatic ductal adenocarcinoma.
  • Greiner, Thomas U.; Hyotylainen, Tuulia; Knip, Mikael; Backhed, Fredrik; Oresic, Matej (2014)