The Nijmegen Breakage Syndrome is a rare DDR-defective syndrome due to mutations of NBS1, a member of the MRN complex. It is characterized by microcephaly, defective immune responses and cancer predisposition. The neurological features of NBS patients have been modelled in a mouse with central nervous system (CNS) restricted NBS1 knock-out (Nbn-CNS-del mouse), which shows microcephaly, severe ataxia and cerebellar hypoplasia. While the common view speculated that these neurological phenotypes are probably due to impaired proliferation and/or apoptosis of neural progenitor cells, caused by accumulation of toxic replication intermediates and damaged DNA left unrepaired by a dysfunctional MRN complex, we propose an innovative and non-necessarily alternative hypothesis, that is: NBS1 might exert additional functions in organelles essential for Central Nervous System development. Indeed, our preliminary data indicate that NBS1-KO induces morphological alterations of the primary cilium (PC) in several cell models and an impairment of the SHH pathway, a PC-dependent pathway essential for cerebellar granule precursor cells (GCPs) expansion, in primary GCPs cultures. Scattered observations in the literature support this hypothesis. To better sustain it, we will pursue to evaluate the following objectives: 1) how NBS1 mechanistically regulates PC; 2) whether the functions of NBS1 involved in PC regulation are DDR dependent; 3) whether there is PC dysfunction in Nijmegen Breakage Syndrome patients. Experimentally, we will use several cellular models, part of which has been (or is being) specifically developed in the lab for this project.
This work thereby aims to provide new insights into the emergent role of NBS1 on PC which could shed a light on the striking neurological phenotypes that manifest in the rare human disorder Nijmegen Breakage Syndrome and will further increase our understanding of the role of DDR proteins in neuronal development.
This work thereby aims to provide new insights into the emergent role of NBS1 on PC which could shed a light on the striking neurological phenotypes that manifest in the rare human disorder Nijmegen Breakage Syndrome and will further increase our understanding of the role of DDR proteins in neuronal development.
NBS neurological phenotype has no cure, at the present. Although we are unable to propose a therapeutic strategy, we are fairly confidentthat only a significant step forward in understanding its molecular basis may allow the design of an appropriate intervention strategy, in a close future.