New insights in pathophysiology and therapy of immune-mediated fibrosing cholangiopathies / Genetics of Parkinsons disease: from molecular mechanisms to personalized therapies

New insights in pathophysiology and therapy of immune-mediated fibrosing cholangiopathies

Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and IgG4-related cholangitis (IRC) are major immune-mediated fibrosing cholangiopathies. While PBC affects small intrahepatic bile ductules <100 m diameter, PSC and IRC mainly damage larger extra- and intrahepatic bile ducts leading to fibrotic bile duct stenoses. When untreated, these enigmatic hepatobiliary diseases have a progressive course and affected individuals may develop biliary cirrhosis and die of complications of cirrhosis or terminal liver failure. PBC typically affects middle-aged women (up to 90%), PSC mainly younger men and adolescents (~70%), often associated with inflammatory bowel disease (~70%), and IRC mainly elderly males (>80%). The potential contributions of genetic, environmental, immunological and other endogenous factors have intensely been studied in the recent past. Among those, the potential pathogenic role of hydrophobic human bile acids is under intense discussion. Guideline-supported therapies beneficially affect the disease course and symptoms in PBC and IRC. Additional novel therapeutic approaches await approval by authorities or are under study.

Genetics of Parkinsons disease: from molecular mechanisms to personalized therapies

Since the discovery that rare mutations in the gene encoding the alpha-synuclein (SNCA) can cause an autosomal-dominantly inherited form of Parkinson’s disease 25 years ago, many aspects of the complex genetic architecture of this common neurodegenerative syndrome have been unraveled.  Variants in the LRRK2 and GBA1 genes are the most common disease causing mutations or strong genetic risk factors, but more than 90 genetic risk loci have been identified by genome wide association studies (GWAS). It has been demonstrated that fundamental cellular pathways, like lysosomal protein clearance, endovesicular transport and mitochondrial quality control contribute to both familial and sporadic PD, although probably to different degrees. Based on these discoveries, targeted disease course modifying treatments are being developed for specific subgroups of patients.