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Browsing by discipline "Molekyylineurologia"

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  • Heterozygous TYROBP deletion (PLOSLFIN) is not a strong risk factor for cognitive impairment 
    Kaivola, Karri; Jansson, Lilja; Saarentaus, Elmo; Kiviharju, Anna; Rantalainen, Ville; Eriksson, Johan G.; Strandberg, Timo E.; Polvikoski, Tuomo; Myllykangas, Liisa; Tienari, Pentti J. (2018)
    Biallelic loss-of-function mutations in TYROBP and TREM2 cause a rare disease that resembles early-onset frontotemporal dementia with bone lesions (PLOSL). Some PLOSL-causing variants in TREM2 have also been associated with Alzheimer’s disease when heterozygous. Here, we studied the PLOSLFIN TYROBP deletion that covers four of the gene’s five exons. We genotyped 3220 older Finns (mean age 79, range 58-104) and found 11 deletion carriers (mean age 78, range 60-94). The carrier prevalence was 0.0034 (1 in 293) that matches previous findings in younger cohorts suggesting no significant early mortality. By comparing MMSE scores and diagnoses of dementia we did not find any significant differences between TYROBP deletion carriers and non-carriers (all p-values >0.5). Neuropathological analysis of two deletion carriers (aged 89 and 94) demonstrated only minimal beta-amyloid pathology (CERAD score 0). Collectively these results suggest that heterozygous carriership of the TYROBP deletion is not a major risk factor of dementia.
  • Metabolic Consequences of Folate Deficiency in Mice 
    Hovinen, Topi (2016)
    Folate deficiency (FD) has been found to cause number of medical conditions varying from megaloblastic anemia to fetal neural tube defects but the molecular basis behind these has remained poorly understood. We studied the metabolic consequences of FD in mouse liver and brain, concentrating on transsulfuration pathway and cysteine-dependent pathways. Data was acquired with mass spectrometry based metabolomics and western blotting. We found that FD induces lack of cysteine in liver and brain, causing further imbalances in cysteine-derived metabolites such as glutathione and taurine. Changes in enzyme expression show that hepatic cells prioritize glutathione synthesis over taurine synthesis, while the brain does vice versa. We then supplemented FD mice with N-acetylcysteine (NAC), precursor of cysteine. NAC supplementation restored hepatic bile acid and blood glutathione levels of FD tissues. These results improved our understanding of FD induced metabolic imbalances and proved that NAC significantly rescues some of these changes.

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