Malfunctioning DDR and metabolism drive cerebellar pathologies in genetic instability disorders

• Applicant: Professor Dr. Christoph Englert, since 4/2023
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; General Genetics and Functional Genome Biology ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465316902

The genome is constantly challenged by endogenous and exogenous damaging insults. Cells evolve two key DNA damage response (DDR) pathways, which are mediated by ATM and ATR. The MRN (MRE11/RAD50/NBS1) complex functions mainly to activate ATM in response to DNA double strand breaks (DSBs) and also regulates the ATR activation in response to replication stress. Mutations of ATM, ATR, NBS1 and MRE11 cause Ataxia-Telangiectasia (A-T), Seckel Syndrome (SS), Nijmegen Breakage Syndrome (NBS) and A-T Like Disorder (A-TLD), respectively. A-T and A-TLD are associated with cerebellar degeneration, NBS and ATR-SS are characterized by microcephaly and mental retardation. It is well known yet puzzling that mutations of DDR molecules and repair pathways cause neurological symptoms, which are often associated with defects in the cerebellum, leading to ataxia in human patients and mouse models; however, why cerebella, but not cerebral cortex, are vulnerable to DDR malfunction is a long-term unsolved mystery. To understand the molecular pathways of these disorders, Nbs1, Mre11, Atm, and Atr mutant mouse models have been generated. We found that although surprisingly Atr, Nbs1 and Mre11 are not required for survival of postmitotic neurons, they have other novel physiological functions, for example in mitochondria and metabolism, vascular integrity and presynaptic activities. We hypotheses that neurological defects of these genomic instability disorders A-T, SS, A-TLD and NBS are developmental as well as metabolic disorders and that these disorders are caused by the failure of the canonical as well as the non-canonical functions of these DDR players. We therefore set up the following objectives: (1) To study the molecular pathways that render the cerebellar neuroprogenitors susceptible to the DDR malfunction (2) To elucidate the function of metabolism as a regulator of cerebellar attrition of DDR deficiency(3) To discover and characterize the environmental factors such as vascular integrity in preventing cerebellar defects We will take the following approaches: (i) Molecular and genetic dissection of the DDR in cerebellar development and maintenance. (ii) Integrated omics including targeted metabolic analysis and single cell RNA-seq in neuron and non-neuronal cells as well as neuronal activity. (iii) Molecular and imaging analyses of vascular integrity in cerebella in comparison with cerebral cortices.Our study will lead to new discovery of molecular pathways that under control by the DDR proteins in neuropathies particularly the specificity of cerebella in genomic instability syndromes. The understanding of the nature of the ataxia related disorders will not only deliver pharmaceutical strategies for the individuals, but also shed light on the fundamental biology of the cerebellum development, functionality and its maintenance.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Ari Barzilai, Ph.D.
• Ehemaliger Antragsteller: Professor Dr. Zhao-Qi Wang, until 3/2023