DNA repair & cognitive function

1 PhD project offered in the IPP summer call 2021

This project is part of the Science of Healthy Ageing Research Programme (SHARP).

Scientific background

Efficient DNA repair is one of the most important factors that prevent premature ageing. Moreover, defects in many DNA repair pathways influence neural function, suggesting a substantial contribution to the maintenance of the nervous system. Since neurogenesis is critical not only in the developing brain, but also during adulthood in supporting long-term memory, age-related cognitive decline may well be linked to problems in genome integrity. However, the mechanisms by which DNA repair pathways protect neuronal function are still poorly understood.

BRCA2 is a DNA repair factor with prominent roles in homologous recombination and the management of replication stress. Heterozygous mutations are associated with familial breast and ovarian cancer. Compound heterozygous or homozygous mutations cause Fanconi anemia Type D, a congenital disease accompanied by microcephaly, developmental delay and intellectual disability. Consistent with an important role of BRCA2 in brain function, Fanconi anemia mouse models show neural stem cell exhaustion and premature ageing. Based on observations of more subtle neuropsychiatric problems and intellectual disability among patients with heterozygous BRCA2 mutations, the Schweiger and Ulrich labs have combined their respective expertise in human genetics, neurological disorders and the molecular biology of genome stability. In this collaboration, we aim to elucidate the underlying mechanisms that link this prominent DNA repair protein to cognitive function and decline.

PhD project: Role of BRCA2 in age-related cognitive decline

In this project, supervised jointly by Susann Schweiger at the University Medical Center and Helle Ulrich at the Institute of Molecular Biology, we will examine the consequences of BRCA2 heterozygosity under the influence of a set of environmental factors. On the cellular level, the PhD student will characterize DNA replication and repair capacities in induced pluripotent stem (iPS) cells from patients and cell lines engineered by CRISPR/Cas. The iPS cells will be differentiated into neural precursor cells and neurons as well as cerebral organoids. In this setting, the student will investigate environmental effects on neuronal development, proliferation, migration and apoptosis. On the organismic level, consequences of BRCA2 depletion for brain development will be probed and behavior and cognitive function in BRCA2 heterozygous mice will be studied during ageing. These experiments will provide insight into the mechanistic basis of the vulnerablility of affected individuals towards neurodevelopmental problems and premature decline.

If you are interested in this project, please select Susann Schweiger as your group preference in the IPP application platform.

Publications relevant to this project

Cooper A, Butto T, Hammer N, … & Schweiger S (2020) Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome. Nat Commun, 11:480 Link

Deciphering Developmental Disorders Study (2017) Prevalence and architecture of de novo mutations in developmental disorders. Nature, 542:433–438 Link

Arnoux I, Willam M, Griesche N, …, Schweiger S & Stroh A (2018) Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease. eLife, 7:e38744 Link

Sriramachandran AM, Petrosino G, Mendez-Lago M, Schafer AJ, Batista-Nascimento LS, Zilio N & Ulrich HD (2020) Genome-wide nucleotide-resolution mapping of DNA replication patterns, single-strand breaks, and lesions by GLOE-Seq. Mol Cell, 78:975-985 Link

Wong RP, Garcia-Rodriguez N, Zilio N, Hanulova M & Ulrich HD (2020) Processing of DNA polymerase-blocking lesions during genome replication is spatially and temporally segregated from replication forks. Mol Cell, 77:3-16 Link

Contact

Prof. Susann Schweiger (If you are interested in this project, please select Susann Schweiger as your group preference in the IPP application platform.)

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Prof. Helle Ulrich

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