Generation of a null allele and humanized containing human disease-variants.

Clinical variants of are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and other degenerative diseases. The predicted ortholog of is encoded by , but functional orthology has not been demonstrated We undertook CRISPR/Cas9-based genome editing of the locus to create a complete loss of function allele; all exons and introns were deleted, creating , which resulted in neurodegeneration after oxidative stress. Next, we undertook CRISPR-based genome editing to replace exons with human TARDBP coding sequences, creating humanized ( ) expressing TDP-43 Based on the efficiency of this genome editing, we suggest that iterative genome editing of the target locus using linked coCRISPR markers, like , would be a more efficient strategy for sequential assembly of the large engineered transgenes.

SGPL1 stimulates VPS39 recruitment to the mitochondria in MICU1 deficient cells.

Objective: Mitochondrial "retrograde" signaling may stimulate organelle biogenesis as a compensatory adaptation to aberrant activity of the oxidative phosphorylation (OXPHOS) system. To maintain energy-consuming processes in OXPHOS deficient cells, alternative metabolic pathways are functionally coupled to the degradation, recycling and redistribution of biomolecules across distinct intracellular compartments. While transcriptional regulation of mitochondrial network expansion has been the focus of many studies, the molecular mechanisms promoting mitochondrial maintenance in energy-deprived cells remain poorly investigated.

Structure of human brain fructose 1,6-(bis)phosphate aldolase: linking isozyme structure with function.

Fructose-1,6-(bis)phosphate aldolase is a ubiquitous enzyme that catalyzes the reversible aldol cleavage of fructose-1,6-(bis)phosphate and fructose 1-phosphate to dihydroxyacetone phosphate and either glyceral-dehyde-3-phosphate or glyceraldehyde, respectively. Vertebrate aldolases exist as three isozymes with different tissue distributions and kinetics: aldolase A (muscle and red blood cell), aldolase B (liver, kidney, and small intestine), and aldolase C (brain and neuronal tissue). The structures of human aldolases A and B are known and herein we report the first structure of the human aldolase C, solved by X-ray crystallography at 3.