engleski

Dysfunction of the endolysosomal pathway is a common feature of neurodegenerative diseases

Niemann-Pick type C disease (NPC) is a rare inherited lysosomal storage disorder characterized by cholesterol accumulation leading to progressive neurodegeneration and neuroinflammation. It is intriguing that this rare monogenic disease (caused by mutations in NPC1/ NPC2 genes) shows several key features of a complex Alzheimer's disease (AD). Using NPC disease cellular and animal models our goal is to elucidate both common and specific pathways involved in neurodegeneration and/or neuroinflammation in NPC and AD. We showed that proteolysis by a key AD protease BACE1 is enhanced in NPC1-null cells/neurons as well as in NPC1-null mouse brains, and is mostly likely due to a defect within the endolysosomal transport resulting in accumulation of BACE1 and its substrates in endocytic compartments. Moreover, we detected impaired retromer function in NPC. Changes in retromer distribution in NPC1 mouse brains were observed already at presymptomatic stage (at 4-weeks of age), indicating that retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverted retromer dysfunction, suggesting that retromer impairment in NPC is mechanistically dependent on cholesterol accumulation. We propose that rescue of retromer impairment may represent a novel therapeutic approach against NPC, in addition to AD. The knowledge gained through this work could have a broader impact since defects of endolysosomal pathway are shared by other rare lysosomal storage disorders as well as the more common neurodegenerative disorders, such as Alzheimer's and Parkinson's disease.

Alzheimer's disease ; endolysosomal pathway ; neurodegeneration ; NPC1 ; rare diseases

nije evidentirano