The biochemical basis for genetically-inherited Frontotemporal Dementia with TDP-43 pathology.

Abstract

Frontotemporal Dementia (FTD) is a highly heritable form of younger-onset dementia and a majority of inherited cases can be attributed to heterozygous loss of GRN or hexanucleotide repeat expansions in the C9orf72 gene. The pathogenic basis for FTD caused by either of these gene mutations is still under investigation, however current evidence suggests that neurodegeneration in FTD caused by GRN mutations (FTD-GRN) ensues from disrupted lysosomal lipid catabolism, whereas the neurodegenerative trigger in FTD-C9orf72 cases remains indeterminate.

This thesis investigates the biochemical basis for FTD caused by GRN and C9orf72 mutations in post-mortem tissue from heavily affected frontal lobe and less affected parietal lobe, and the potential of peripheral myelin lipids as FTD biomarkers through the development of an isomer separation method to quantify the myelin lipid galactosylceramide in plasma.

Lipidomic analysis demonstrated pronounced myelin-enriched sphingolipid loss in the frontal white matter of FTD-GRN cases, with a similar, but less-pronounced loss observed in FTD-C9orf72 cases. FTD-GRN cases were distinguished from FTD-C9orf72 cases by marked cholesterol ester accumulation in white matter and acylcarnitine accumulation in the grey matter, suggestive of mitochondrial dysregulation. Evidence of phagocytic microglia were identified in both FTD groups while increased activity of sphingolipid catabolic enzymes was observed in FTD-GRN cases alone.

Proteomic analysis confirmed mitochondrial dysfunction and identified increased abundance of phagosome maturation and decreased abundance of synaptic signalling and mevalonate pathway proteins in both FTD groups, although these changes were more pronounced in FTD-GRN cases.

Finally, we demonstrate that the myelin galactosphingolipids are significantly lower in plasma of FTD cases, establishing the potential for these lipids to serve as diagnostic and prognostic plasma biomarkers in FTD.