All ETDs from UAB

Advisory Committee Chair

Erik Roberson

Advisory Committee Members

Laura Volpicelli-Daley

Andrew Arrant

Paul Gamlin

Farah Lubin

David Standaert

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) School of Medicine

Abstract

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.

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