Role of mitochondrial dynamics and autophagy in the pathogenesis of Primary Biliary Cholangitis (PBC): novel insights and therapeutic opportunities / Targeting the ER stress in ALS models by MDFA family of compounds

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that affects mostly middle age women (90%) and is associated with the immune-mediated destruction of small to medium size intrahepatic bile ducts, likely as a result of loss of tolerance to mitochondrial antigens. An important disease hallmark, present in more than 90% of the patients, is the development of serum antimitochondrial antibodies (AMAs) against PDC-E2, which is aberrantly overexpressed in the cytoplasm and plasma membrane of cholangiocytes. We have previously reported that the expression of microRNA-506 (miR-506) is increased in PBC cholangiocytes, targeting the Cl⁻/HCO3⁻ exchanger AE2 and leading to intracellular pH (pHi) disturbances and PBC-like features, including PDC-E2 overexpression and immune activation. Autophagy, and specifically mitophagy, is a critical cell-intrinsic, quality-control and anti-inflammatory mechanism necessary to eliminate dysfunctional organelles, such as mitochondria. These processes are critically dependent on pHi, but their role in PBC remains unknown. Our aim was to characterize the mitochondrial dynamics and auto(mito)phagy processes in PBC and evaluate their contribution to disease pathogenesis.

Neurodegenerative diseases (NDDs) are characterised by progressive neuronal loss and are currently incurable. Some of the most common NDDs, such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and ALS, are characterised by deficits at various stages in the processing and recycling of misfolded proteins such as beta-amyloid, tau or TDP-43, which have been described as main hallmarks of these diseases.

Although the ultimate effector for the degradation of non-functional organelles and aberrant proteins is the lysosome, the endoplasmic reticulum is key for their correct processing. Both organelles interact to maintain cellular homeostasis, particularly in protein and lipid metabolism.

Up to date, the therapeutic strategies used have mainly been based on hallmark-against strategies, with disappointing results. Therefore, the development of new non-hallmark-based disesase-modifying treatments requires alternative strategies. In NDDs such as ALS, the integrated stress response is severely altered, and Miaker Developments has developed a new family of molecules (MDFA) that promote the maintenance of endoplasmic reticulum homeostasis.

This study will evaluate in vitro the toxicity and efficacy of MDFA family of compounds and in vivo in a Drosophila melanogaster model that expresses human TDP-43 specifically in glial cells.