Defective Lysosomal Lipid Catabolism as a Common Pathogenic Mechanism for Dementia

Defective Lysosomal Lipid Catabolism as a Common Pathogenic Mechanism for Dementia.

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Item Type: Review
Status: Published
Official URL:
Journal or Publication Title: NeuroMolecular Medicine
Volume: 23
Number: 1
Page Range: pp. 1-24
Date: 2021
Divisions: Lipid Metabolism and Neurochemistry
Depositing User: General Admin
Identification Number: 10.1007/s12017-021-08644-4
ISSN: 1535-1084
Date Deposited: 10 Jun 2021 05:57

Dementia 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 processes as major risk determinants for AD, with the most significant being inheritance of the ε4 allele of the APOE 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 the APOE ε4 allele, and heterozygous loss of function mutations in the GBA gene, encoding the lysosomal catabolic enzyme glucocerebrosidase; whilst heterozygous mutations in the GRN gene, required for lysosomal catabolism of sphingolipids, are responsible for a significant proportion of FTD cases. Homozygous mutations in the GBA or GRN 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 sufficient to produce the pathological hallmarks of dementia, indicating that defective lipid catabolism is a common mechanism in the etiology of dementia.

Lee, Jun Yup
Marian, Oana C.
Don, Anthony S.
Last Modified: 10 Jun 2021 05:57

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