Biology subjects

Khaled, H.

Publications and source records attributed to Khaled, H..

2 recordsLinked to original sources

bioRxiv2022

SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology

Amyloid-{beta} oligomers (A{beta}Os), toxic peptide aggregates found in Alzheimers disease (AD), cause synapse pathology. A{beta}Os interact with Neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in A{beta} pathology was previously unstudied. Here, we show competitive interaction of SorCS1 and A{beta}Os with {beta}-NRXs and rescue effects of SorCS1 on A{beta}O-induced synaptic pathology. Like A{beta}Os, SorCS1 binds to NRX1{beta} through the histidine-rich-domain (HRD) of NRX1{beta}, and SorCS1 and A{beta}Os compete for NRX1{beta} binding. In cultured hippocampal neurons, SorCS1 colocalizes with NRX1{beta} on the axon surface, and axonal expression of SorCS1 rescues A{beta}O-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling as well as A{beta}O-induced structural defects in excitatory synapses. Thus, we reveal a role of SorCS1 in the rescue of A{beta}O-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for AD.

neuroscience↗

bioRxiv2018

FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice.

DNA double-strand breaks (DSBs) can be repaired by two major pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). DNA repair pathway choice is governed by the opposing activities of 53BP1, in complex with its effectors RIF1 and REV7, and BRCA1. However, it remains unknown how the 53BP1/RIF1/REV7 complex stimulates NHEJ and restricts HR to the S/G2 phases of the cell cycle. Using a mass spectrometry (MS)-based approach, we identify 11 high-confidence REV7 interactors and elucidate the role of a previously undescribed factor, FAM35A/SHDL2, as a novel effector of REV7 in the NHEJ pathway. FAM35A depletion impairs NHEJ-mediated DNA repair and compromises antibody diversification by class switch recombination (CSR) in B-cells. FAM35A accumulates at DSBs in a 53BP1-, RIF1- and REV7-dependent manner and antagonizes HR by limiting DNA end resection. In fact, FAM35A is part of a larger complex composed of REV7 and another previously uncharacterized protein, C20orf196/SHDL1, which promotes NHEJ and limits HR. Together, these results establish FAM35A as a novel effector of REV7 in controlling the decision-making process during DSB repair.

cancer biology↗