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The roles of progranulin and TMEM106B in lysosomal physiology and neurodegenerative disease

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Abstract

Frontotemporal lobar degeneration (FTLD) is a devastating, clinically heterogeneous neurodegenerative disease that results in the progressive atrophy of the frontal and temporal lobes of the brain. Most often presenting with drastic alterations in personality and behavior, as well as a gradual decline in language capabilities, FTLD is the second leading cause of early-onset dementia only after Alzheimer’s disease. One of the major causes of familial FTLD is haploinsufficiency of the protein, progranulin (PGRN), resulting from mutation in the granulin (GRN) gene. Interestingly, PGRN shows a dosage-dependent disease correlation, and GRN mutation resulting in complete loss of PGRN causes the lysosomal storage disease (LSD), neuronal ceroid lipofuscinosis (NCL). In this text, my co-workers and I demonstrate that PGRN is proteolytically processed in the lysosome into discrete granulin peptides, which may possess distinct functions. We have independently found interactions between PGRN or granulin peptides and three lysosomal hydrolases: Cathepsin D (CTSD), glucocerebrosidase (GBA), and ɑ-N-acetylgalactosaminidase (NAGA). The activity of each of these enzymes was found to be reduced in Grn-/- mice, indicating that a potential mechanism of PGRN-related disease may be dysfunction of multiple lysosomal hydrolases. In addition to possessing an indeterminate lysosomal function, PGRN has also been shown to be a neurotrophic factor. Completion of a high-throughput screen searching for the receptor that mediates this function identified cluster of differentiation 68 (CD68) and neuropilin 2 (NRP2) as putative PGRN receptors. A second protein that has become of interest to the study of FTLD is TMEM106B. Variants of TMEM106B have been associated with an increased risk of developing FTLD, especially in cases of GRN mutation (FTLD-GRN). Although TMEM106B is known to be an endolysosomal transmembrane protein that regulates lysosomal morphology and degradative capacity, its exact function is unclear. Our current findings suggest that TMEM106B may regulate cellular levels of the phosphoinositide, PI(3,5)P2. In summary, our work supports a lysosomal role of the FTLD- and NCL-related protein, PGRN, and identifies a novel function of the FTLD risk factor, TMEM106B.

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Date Issued

2018-05-30

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Keywords

Neuronal ceroid lipofuscinosis; Progranulin; TMEM106B; Lysosome; Cellular biology; Molecular biology; Frontotemporal lobar degeneration; Neurodegeneration

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Committee Chair

Hu, Fenghua

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Committee Member

Lin, David M.
Bynoe, Margaret S.
Libert, Sergiy

Degree Discipline

Comparative Biomedical Sciences

Degree Name

Ph. D., Comparative Biomedical Sciences

Degree Level

Doctor of Philosophy

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Government Document

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Attribution-NonCommercial-NoDerivatives 4.0 International

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dissertation or thesis

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