Too Clingy: Extra Hydrogen Bond Prompts Protein Aggregation
Certain mutations in TDP-43, tau, and NfL add one hydrogen bond to their low-complexity domains. This warps phase transition and strengthens self-aggregation.
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Certain mutations in TDP-43, tau, and NfL add one hydrogen bond to their low-complexity domains. This warps phase transition and strengthens self-aggregation.
TDP-43 inclusions in intramuscular nerve bundles, paired with clinical criteria, may enable diagnoses at early stages of ALS.
Adeno-associated viruses carrying Cas9 and guide RNAs cut hexanucleotide repeats out of the C9ORF gene. RNA inclusions and poly-dipeptides became sparse.
A provocative new study suggests that unlike in mice, TSPO in people does not rise with microglial activation; instead, a higher PET signal reflects more microglia.
Cryo-electron tomography reveals amorphous blobs of TDP-43 C-terminal fragments. They ensnare stalled proteasomes in the cytosol.
Neurons need LRRK2 in order to take up tau from the extracellular milieu. In ALS neurons, tau scuppers mitochondria, whereas in healthy cells it helps the nucleolus to function correctly.
Without TREM2, microglia remained trapped in a homeostatic state and failed to clear TDP-43 aggregates. In a surprising twist, the two proteins were found to interact.
Cryo-EM revealed that TDP-43 protofilaments from people with ALS/FTD formed the same structure, with a core of stacked double spirals. It is wildly different from that of TDP-43 filaments made in vitro, and from those of other amyloids.
In a tiny Phase 3 trial of the ASO tofersen, a neurodegeneration marker changed in the right direction. Trends on other endpoints favored drug. Still, the trial was negative. Next steps for tofersen remain up in the air.
Typically a sign of viral infection, double-stranded RNAs were spotted in C9ORF72 carriers, in whom they mingled with cytoplasmic TDP-43 inclusions. In mice, dsRNAs spread between connected neurons, provoking Type I interferon response and killing cells.
Scientists linked genetic risk variants with protein changes in Alzheimer’s brain, cerebrospinal fluid, and plasma. They identified known drugs that target some of them.
The iPSC Neurodegenerative Disease Initiative is creating 100+ isogenic cell lines. Each carries a different risk variant for Alzheimer's or a related dementia. Scientists around the world can obtain the cells through Jackson Labs.
By comparing protein changes with GWAS data, scientists identified new links to AD. This method can unearth genes that otherwise fall short of genome-wide significance.
Breaking familiar gene-disease patterns, HTT trinucleotide expansions lead to huntingtin aggregates in prefrontal cortex. Noncoding caveolin 1 variants suppress its expression.
Topline results suggested that the anti-inflammatory treatment stabilized cognition and function over six months. The trial did not include biomarkers.