Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) School of Medicine
Frontotemporal dementia (FTD) is a leading cause of early-onset dementia and has a significant socioeconomic burden due to difficulties in diagnosis and delay to diagnosis. FTD is a clinically, pathologically, and genetically heterogeneous disorder. The pathological changes associated with FTD are termed frontotemporal lobar degeneration (FTLD). Protein aggregates are always present in FTLD, with >90% of cases presenting with either TDP-43 or tau pathology. Most cases of FTD are sporadic, but familial cases account for up to 25% of FTD. All familial FTD is inherited in an autosomal dominant fashion with most cases being caused by mutations in tau (MAPT), C9ORF72, or progranulin (GRN). Heterozygous loss-of-function mutations causal for FTD-GRN result in progranulin haploinsufficiency. Progranulin is a secreted and lysosome-resident glycoprotein involved in the regulation of numerous lysosomal enzymes. Here, we describe how loss of progranulin deficiency causes impairment of acid sphingomyelinase (aSMase) in Grn–/– mice and how FTLD with TDP type A, regardless of progranulin mutation, is associated with reduction of neutral sphingomyelinase 2 (nSMase2). We then demonstrate that progranulin interacts with aSMase but not nSMase2, but both aSMase and nSMase2 interact with a lipid species which is critical for lysosomal dysfunction and deficient in FTD-GRN, bis(monoacylglycero)phosphate. We then discuss the different mechanisms by which these enzymes may be deficient. Together, these data provide iv insight into novel lysosomal abnormalities caused by progranulin deficiency and non-lysosomal abnormalities found in genetic and sporadic FTD.
Boyle, Nicholas R., "Reduction of Sphingomyelinases Associated with Progranulin Deficiency and Frontotemporal Dementia" (2023). All ETDs from UAB. 443.