Parkinson’s disease, gastric ulcer… One picture to understand the potential targets for clinical translation of recent brain and gastrointestinal diseases

▎WuXi AppTec Content Team Editor

The first step behind every successful clinical drug development comes from the efforts of scientists in the laboratory, and the first step is to identify suitable targets to develop corresponding treatments. drug. In today’s article, the WuXi AppTec content team takes stock of the articles recently published in various top scientific journals that have the potential to become targets for the treatment of neuromuscular, gastrointestinal and other diseases, in order to provide a reference for the research and development of the industry!


Diseases:Parkinson’s disease

Discovery: The lysosome relies on its V-ATPase function to cause proton influx, and a yet-to-be-discovered The proton loss pathway maintains the pH of the lysosomal lumen between 4.5 and 5.0 for efficient digestion of macromolecules in the lumen. We found that TMEM175 can act as a proton-activated and proton-selective channel (LyPAP) on the lysosomal membrane to mediate lysosomal proton loss. TMEM175 was previously considered a genetic risk factor for Parkinson’s disease. Excessive acidification of the lysosome activates LyPAP, and an endogenous polyunsaturated fatty acid and synthetic agonist can also activate TMEM175 to release protons in the lysosome. Deletion of TMEM175 causes excessive acidification of lysosomes and affects proteolysis, which in turn promotes the accumulation of α-synuclein, a neuropathological feature of Parkinson’s disease. Therefore, by regulating TMEM175 or lysosomal lumen pH, it has the potential to regulate lysosomal degradation and the progression of Parkinson’s pathology.


Disease:periventricular heterotopia (PH)

Discovery: The centrosome is the junction of the cytoskeleton in the cell and regulates cell division, migration and cilia formation. The researchers used spatial proteomics to analyze the interaction network of neural stem cells (NSCs) derived from human induced pluripotent stem cells and neural cells on the centrosome protein. When analyzing a cohort of neurodevelopmental disorders, the researchers found many variations in proteins on the NSC centrosome in patients with paraventricular heterotopia. When the researchers expressed the PRPF6 variant protein, they could replicate the ventricular heterotopia in the developing mouse brain. Since PRPF6 is involved in the splicing of pre-mRNA, this suggests that mis-splicing of microtubule-associated kinase transcripts on the centrosome is necessary for the development of brain disease manifestations, and mutant PRPF6 may be a potential target.


Disease:brain injury

Finds: Uncontrolled inflammation after brain injury is associated with increased risk of epilepsy and cognitive impairment, while the thalamus in the brain It is the part of the brain that is particularly vulnerable to such damage after a brain injury. The researchers found that in mouse models, thalamic inflammation alone is sufficient to trigger the negative effects of brain damage, such as hyperstimulation of cells and circuits, and increased risk of epilepsy. This phenomenon is caused by down-regulation of the GABA transport protein GAT3 in thalamic astrocytes. While increasing expression of GAT3 protein in thalamic astrocytes reduces epilepsy risk, restores cortical status and protects patients with severe chemoconvulsant in a mouse model of brain injury epilepsy and death. GAT3 expression may therefore help reduce the negative effects of brain damage.


Disorders:Aicardi–Goutières syndrome (AGS)

Discovery: RNA1 adenosine deaminase (ADAR1) is an RNA editing enzyme that restricts the production of endogenous immunostimulatory double-stranded RNA (dsRNA) accumulation. Decreased ADAR1 activity in humans results in a severe early-onset rare genetic inflammatory disorder called Icardi-Guterres Syndrome (AGS), which primarily affects the brain and skin. ADAR1 mutations in patients with AGS cause autoinflammatory responses in mice. Two papers published in the same issue of Nature found that ADAR1 inhibits the L-Z-nucleic acid sensor protein ZBP1. ZBP1 can promote type 1 interferon (IFN) activation. ZBP1 induces caspase-8 (caspase-8)-dependent apoptosis and MLKL-mediated necroptosis in ADAR1-deficient cells. We found that the Zα domain of ADAR1 promotes A-to-I base editing, preventing double-stranded RNA (dsRNA) formation and subsequent ZBP1 protein activation. Therefore, targeting ZBP1 has the potential to treat ZBP1-mediated interferonopathies caused by ADAR1 mutation in AGS patients.


Disorders:Irritable Bowel Syndrome (IBS)

Finding: The microbes in the gut are one of the causes of chronic, painful gut discomfort, including IBS, but the detailed mechanisms remain unclear. Researchers have found that histamine, a neuroimmune regulator produced by gut bacteria, causes abdominal pain in a mouse model of IBS.External pain. Mechanistically, bacterial histamine can attract mast cells to the colon by activating histamine 4 receptor (HRH4), making them highly sensitive. The histamine-releasing Klebsiellaaerogenes bacteria were found in large quantities in the stool of IBS patients, and inhibition of HRH4 with drugs can reduce the accumulation of mast cells in the colon and intestinal sensitivity in mice. Therefore lowering bacterial histamine or targeting intestinal histamine 4 receptors may help improve IBS symptoms.


Disease:peptic ulcer

Findings: Peptic ulcers are a common clinical problem that can lead to serious complications such as bleeding or perforation. The secretion of gastric acid is one of the decisive factors in causing peptic ulcer, and its secretion is controlled by gastrin produced by G cells in the stomach. The researchers found that the semaphorin and plexin signaling pathways can inhibit the secretion of gastrin from G cells, thereby limiting the secretion of gastric acid caused by food, and the RasGTPase activating protein RASAL1 is this signaling pathway the central mediator. In addition, RASAL1 was also found to be associated with the disease course caused by non-steroidal anti-inflammatory drugs (NSAIDs), the main risk factor for peptic ulcer in humans. Therefore, drugs targeting RASAL1 have the potential to inhibit gastric acid secretion and relieve peptic ulcer.

We hope that these excellent research results can be translated into clinical practice as soon as possible, bringing different treatment options and possible improvement of life quality to patients with various diseases!

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