Mixed Messages: mRNA Splicing Errors May Promote Alzheimer’s
A large-scale expression study finds mis-splicing of a specific set of genes in AD brain that includes several known risk genes.
NEWS
Intelligence Matters More for Brain Reserve, but Education Helps
Longitudinal and genetic studies reveal that intelligence underlies cognitive reserve.
Sans Synuclein Tetramers, Mice Mimic Parkinson’s Disease
Mutations that destabilize α-synuclein tetramers leave young mice with severe and progressive motor problems resembling those of PD.
Noncoding RNAs Evince World of Gene Regulation in Dopaminergic Neurons
Using TNEs—snippets of RNA transcribed from noncoding regions—as a gauge of enhancer activity, researchers tied Parkinson’s risk variants to gene regulation.
Dipeptide Repeat Proteins Trigger TDP-43 Pathology, Faulty Nuclear Import
In a fly model, C9ORF72 pathology pulls TDP-43 from the nucleus, which leads to disrupted nuclear import and neurodegeneration.
Does APP Promote Synapse Loss, Aβ Production Through Wnt Signaling?
A Wnt pathway inhibitor rescued dendritic spines in cultured neurons and cleared plaques in an AD mouse model.
ALS Gene Tied to Psychiatric and Neurodevelopmental Disease
Families of ALS and FTD patients with C9ORF72 expansions have more mental illness, suggesting the gene affects brain function throughout life.
In Mice, Caspase-1 Inhibitor Quells Inflammation, Aβ, Memory Loss
VX-765 could be a therapeutic candidate for Alzheimer’s disease.
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SPOTLIGHT
Mixed Messages: mRNA Splicing Errors May Promote Alzheimer’s
Add mRNA splicing to the list of what goes awry in AD brain. In a study of 450 postmortem AD and control brains, the amount of neuropathology correlated with alternative splicing or mis-splicing of a small set of transcripts. For some of these transcripts, AD-associated genetic variants correlated with the mis-splicing, hinting at a role for splicing errors in disease pathogenesis.
PD Mouse Model Puts Spotlight on α-Synuclein Tetramers
The theory that destabilization of physiological tetramers contributes to α-synuclein proteotoxicity was put to the test in mice engineered with mutations that break up the multimers. The animals developed severe movement disorders at an early age. Whole-body tremor and L-DOPA responsiveness, worse in males, were reminiscent of Parkinson’s disease.
“TeeNiE” RNAs Unveil Gene Regulation in Neurons
In dopaminergic neurons plucked from nearly 100 postmortem brains, researchers discovered upwards of 70,000 transcribed noncoding elements (TNEs)—snippets of RNA transcribed from the introns of genes. Many of these RNAs hail from active enhancers, and researchers found that disease risk variants tended to land in TNEs or regulate their expression. The study, which pushed the limits of laser capture microdissection and RNA sequencing, might help researchers tie specific enhancer regions to the risk imparted by GWAS variants.
Dipeptide Repeat Proteins Trigger TDP-43 Pathology, Faulty Nuclear Import
A twist has emerged in the debate about C9ORF72 repeat expansions. A new study claims it is not the expanded RNA that is toxic, but the dipeptide repeats it encodes, and only through TDP-43. In fruit flies, the peptides coax TDP-43 from the nucleus into cytoplasm, where it aggregates. This misplaced TDP-43 then disrupts nuclear import, kicking off a cycle of worsening cellular dysfunction.
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