
TDP-43 bodies in ALS linked to ADAR2 and Calpain abnormal behavior - JPLeRouzic
https://www.ncbi.nlm.nih.gov/pubmed/29944911
======
JPLeRouzic
There are different kind of ALS diseases. ALS is not well defined, there are
no quick tests or biomarkers. And once it is diagnosed (usually 2 years after
the onset) the patient lives only two years (but that can vary much).

From a practical point of view there are roughly 50% of patients (pALS) that
carry a mutation on SOD1 gene and most of the rest have TDP-43 bodies
inclusions in their neuron's cytoplasm. Abnormal TDP-43 is also seen in other
CNS diseases such as Alzheimer.

This article tells that abnormal TDP-43 stems from ADAR2 downregulation and
Calpain abnormal activity.

ADAR protein is a RNA-binding protein, which functions in RNA-editing through
post-transcriptional modification of mRNA transcripts by changing the
nucleotide content of the RNA. So affected motor neurons bearing TDP-43
pathology invariably exhibit failure in RNA editing at the GluA2
glutamine/arginine (Q/R) site due to down-regulation of adenosine deaminase
acting on RNA 2 (ADAR2).

The authors tell that exaggerated Ca2+ influx through the abnormal AMPA
receptors overactivates calpain, a Ca2+-dependent protease, that cleaves
TDP-43 into aggregation-prone fragments, which serve as seeds for TDP-43
pathology.

I believe this publication is novel and important in the ALS field, any
comment?

