One review of TDP-43 therapies and a study of how a CXCR3 antagonist rescues ER stress in mice brain

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As there is little interesting news in neurodegenerative research, here is a low-quality review on one of my favorite topics and possibly a better article. You may remember that in early 2019 I made a plea for a TDP-43 genetic therapy. I wrote to roughly 250 scientists in this field, and only a handful responded. I may have absolutely no influence, but it seems to me there was more research in this area in the following years.

TDP-43 proteinopathies are pathological hallmarks in ALS/FTD. In general, aging is a risk factor for ALS/FTD adult-onset neurodegenerative diseases (NDD), as with aging comes protein misfolding and accumulation. Academics differentiate these diseases from the type of protein (or protein fragment) and the localization. In patients these distinctions do not hold: Every aging person has misfolded mislocated proteins of several kinds at the same time, so there is no pure sporadic Alzheimer's or Parkinson's diseases, or ALS. For example, scientists tell of three forms of demence that are linked to TDP-43 (FTD/FTLD, Limbic-predominant age-related TDP43 encephalopathy (LATE), and Hippocampal sclerosis of aging).

Now I think that abnormal cellular stress response, including ER stress, causes misfolded, mislocated protein aggregation so removing those deleterious protein aggregates would not really help. Just look at the 20 years of drug trials to remove amyloïds from the brains of Alzheimer patients.

Yet in this review they are still in this mindset, but they do not look after a genetic therapy, instead, the scientists explore small molecule-based approaches to enhance the clearance of pathological TDP-43.

Small molecule-based approaches are easier to implement and anyway, it fits well the academic agenda: To publish low-cost papers during one semester. enter image description here There is nothing new in the list of drugs the authors list, and they lump in the same basket many unrelated drugs.

Another article is more interesting.

The authors recognize that endoplasmic reticulum (ER) is crucial for maintaining cellular homeostasis, and the synthesis and folding of proteins and lipids. The ER is the ordered membranous network and the first compartment of the secretory pathway, which is responsible for the synthesis, modification, and delivery of biologically active proteins to their proper target sites within the cell cytoplasm and the extracellular milieu. The ER is the entry site for the majority of proteins processed in the secretory pathway. If the influx of nascent, unfolded polypeptides exceeds the folding and/or processing capacity of the ER, the normal physiological state of the ER is perturbed. ER is sensitive to stresses including viral infection, it reduces its processing capability, and results in the accumulation of unfolded/misfolded proteins.

Generation of ER stress and induction of the unfolded protein response (UPR) are generic host responses to flavivirus infection as virus replication occurs in close association with ER-derived membranes. Flaviviruses include Dengue virus, Zika, and Japanese Encephalitis virus (JEV).

Then the authors boldly link UPR activation to inflammation. Then they tell that CXCR3 in linked to inflammation. They then assume that inhibiting CXCR3 would be somewhat beneficial to alleviate UPR activity, and therefore be beneficial to patients. I have a hard time finding this as an example of clear logical reasoning, but at least these guys have done some experiments.

They investigated the molecular insights of replication and inflammation upon Japanese encephalitis(JEV) infection and how AMG487 is rescuing it. In response to this, the authors studied the UPR activation pathways leading to ER stress and the rescue effect of AMG487. AMG487 treatment decreased the phosphorylation of eIF2α, a unique ER stress marker. AMG487 treatment improved ROS-induced inflammation and cell death in JEV-infected mice brains. It's already known that Antagonists to CXCR3 including AMG487 can be useful for treatment against flaviviruses, the novelty here is that AMG487 might decrease UPR activity.

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