Alterations in Autophagy Marker Distribution in Different Genetic Subtypes of Frontotemporal Lobar Degeneration

Heale, Richard

Abstract

Frontotemporal dementia (FTD) is the second most common type of early-onset dementia and is characterised by impairments in language and behavioural changes whilst memory is normally well preserved; it can be clinically subdivided into behavioural variant FTD, progressive non-fluent aphasia and semantic dementia. Underlying these dementia subtypes is a group of diseases that are referred to as frontotemporal lobar degeneration (FTLD). Macroscopically these diseases show cell loss in the frontal and temporal lobes which is accompanied by intracellular protein aggregation, which is used to pathologically differentiate FTLD into subtypes; FTLD-Tau, FTLD-TDP43 and FTLD-FUS. Abnormal accumulation of protein in some neurodegenerative disease has been linked to an impairment in autophagy, a cellular waste disposal process, however, this has not been well studied in FTLD. This study used markers associated with two subtypes of autophagy, macroautophagy (MA) (LC3 and Beclin-1) and chaperone-mediated autophagy (CMA) (Hsc70 and LAMP2a) in order to explore variation in autophagy associated protein distribution in the three most common genetic causes of FTLD: C9orf72, MAPT and GRN. Human tissue from the frontal, temporal and occipital cortex from the Manchester Brain Bank was used to immunohistochemically assess a total of 24 FTLD cases which demonstrated genetic mutations in GRN (7 cases), C9orf72 (8 cases) and MAPT (9 cases), in addition to 8 cases with Alzheimer’s Disease (AD) and 9 no-disease aged controls. Results showed that there was a regional decrease (P< 0.05) in the amount of LC3 and Beclin-1 detected in the hippocampus of FTLD-GRN cases. In addition, this decrease in MA marker detection was observed in all FTLD mutation groups and controls in Layer VI of the frontal grey matter. Moreover, Beclin-1 was also decreased in temporal grey matter of FTLD-GRN cases. No significant differences
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were found between controls and the individual mutation groups for either of the CMA markers, LAMP2a and Hsc70.
The findings suggest a potential regional impairment in the formation of autophagosomes in addition to general impairment in MA initiation in FTLD, whilst the more selective CMA pathway were largely unaffected. Therapies restoring autophagsome formation and maturation therefore may have a therapeutic benefit in FTLD.

Citation

Heale, R. (2023). Alterations in Autophagy Marker Distribution in Different Genetic Subtypes of Frontotemporal Lobar Degeneration. (Thesis). University of Salford

• Thesis Type: Thesis
• Deposit Date: Jul 3, 2023
• Publicly Available Date: Jul 31, 2023
• Award Date: Jun 30, 2023