Biology subjects

Dembele, D.

Publications and source records attributed to Dembele, D..

2 recordsLinked to original sources

bioRxiv2018

BIN1 genetic risk factor for Alzheimer is sufficient to induce early structural tract alterations in entorhinal cortex-dentate gyrus pathway and related hippocampal multi-scale impairments

Genetic factors are known to contribute to Late Onset Alzheimers disease (LOAD) but their contribution to pathophysiology, specially to prodomic phases accessible to therapeutic approaches are far to be understood. To translate genetic risk of Alzheimers disease (AD) into mechanistic insight, we generated transgenic mouse lines that express a [~]195 kbp human BAC that includes only BIN1, a gene associated to LOAD. This model gives a modest BIN1 overexpression, dependent of the number of BAC copies. At 6 months of age, we detected impaired entorhinal cortex (EC)-hippocampal pathways with specific impairments in EC-dentate gyrus synaptic long-term potentiation, dendritic spines of granular cells and recognition episodic memory. Structural changes were quantified using MRI. Their whole-brain functional impact were analyzed using resting state fMRI with a hypoconnectivity centered on entorhinal cortex. These early phenotype defects independent of any changes in A-beta can be instrumental in the search for new AD drug targets.

neuroscience↗

bioRxiv2018

Co-translation drives the assembly of mammalian nuclear multisubunit complexes

AO_SCPLOWBSTRACTC_SCPLOWCells dedicate significant energy to build proteins often organized in multiprotein assemblies with tightly regulated stoichiometries. As genes encoding proteins assembling in the same multisubunit complexes are dispersed in the genome of eukaryotes, it is unclear how multisubunit complexes assemble. We show that mammalian nuclear transcription complexes (TFIID, TREX-2 and SAGA) composed of a large number of subunits but lacking precise architectural details are built co-translationally. We demonstrate that the dimerization domains and their positions in the interacting subunits determine the co-translational assembly pathway (simultaneous or sequential). Our results indicate that protein translation and complex assembly are linked in building mammalian multisubunit complexes and suggest that co-translational assembly is a general principle in mammalian cells to avoid non-specific interactions and protein aggregation. These findings will significantly advance structural biology by defining endogenous co-translational building blocks in the architecture of multisubunit complexes.

molecular biology↗