| 2. |
- Neumann, A., et al.
(författare)
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Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (beta-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.
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| 3. |
- de Pooter, Renée F., et al.
(författare)
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Cutting Edge : Lymphomyeloid-Primed Progenitor Cell Fates Are Controlled by the Transcription Factor Tal1
- 2019
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 202:10, s. 2837-2842
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoid specification is the process by which hematopoietic stem cells (HSCs) and their progeny become restricted to differentiation through the lymphoid lineages. The basic helix-loop-helix transcription factors E2A and Lyl1 form a complex that promotes lymphoid specification. In this study, we demonstrate that Tal1, a Lyl1-related basic helix-loop-helix transcription factor that promotes T acute lymphoblastic leukemia and is required for HSC specification, erythropoiesis, and megakaryopoiesis, is a negative regulator of murine lymphoid specification. We demonstrate that Tal1 limits the expression of multiple E2A target genes in HSCs and controls the balance of myeloid versus T lymphocyte differentiation potential in lymphomyeloid-primed progenitors. Our data provide insight into the mechanisms controlling lymphocyte specification and may reveal a basis for the unique functions of Tal1 and Lyl1 in T acute lymphoblastic leukemia.
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