Defective Lysosomal Lipid Catabolism as a Common Pathogenic Mechanism for Dementia

AbstractDementia poses an ever-growing burden to health care and social services as life expectancies have grown across the world and populations age. The most common forms of dementia are Alzheimer ’s disease (AD), vascular dementia, frontotemporal dementia (FTD), and Lewy body dementia, which includes Parkinson’s disease (PD) dementia and dementia with Lewy bodies (DLB). Genomic studies over the past 3 decades have identified variants in genes regulating lipid transporters and endosomal p rocesses as major risk determinants for AD, with the most significant being inheritance of the ε4 allele of theAPOE gene, encoding apolipoprotein E. A recent surge in research on lipid handling and metabolism in glia and neurons has established defective lipid clearance from endolysosomes as a central driver of AD pathogenesis. The most prevalent genetic risk factors for DLB are theAPOEε4 allele, and heterozygous loss of function mutations in theGBA gene, encoding the lysosomal catabolic enzyme glucocerebrosidase; whilst heterozygous mutations in theGRN gene, required for lysosomal catabolism of sphingolipids, are responsible for a significant proportion of FTD cases. Homozygous mutations in theGBA orGRN genes produce the lysosomal storage diseases Gaucher disease and neuronal ceroid lipofuscinosis. Research from mouse and cell culture models, and neuropathological evidence from lysosomal storage diseases, has established that impaired cholesterol or sphingolipid catabolism is suffic...

Source: NeuroMolecular Medicine - February 7, 2021 Category: Neurology Source Type: research