UNCOVERING THE LYSOSOMAL ROLE OF PROGRANULIN
Lysosomes are the degradative centers of the cell and their dysfunction can give rise to lysosomal storage disorders (LSDs). Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that exhibits the features of LSDs: the aggregation of proteins in endolysosomal compartments and a decrease in lysosomal activity. One of the genetic causes of FTLD has been traced back to the haploinsufficiency of progranulin (PGRN), a secreted glycoprotein comprised of seven and one-half granulin repeats. PGRN can also be processed into discrete granulin peptides, each with its own potential function. PGRN has been shown to be critical for proper lysosome function, but the mechanism is still unclear. Since PGRN’s link to FTLD was established, TMEM106B, a lysosomal transmembrane protein, has been identified as a risk factor for FTLD patients with GRN mutations (FTLD-GRN). TMEM106B levels are increased in cases of FTLD-GRN and the overexpression of TMEM106B results in lysosome enlargement and an increase in transcription factor EB-dependent (TFEB) lysosomal exocytosis. TFEB is the transcription factor responsible for the expression of most genes associated with lysosomal biogenesis and its transcriptional activity is increased in ΔGRN cells. Since an increase in TFEB activity is linked to an increase in exocytosis, I hypothesized that the depletion of PGRN results in an increase in lysosomal exocytosis. I assessed whether lysosomal exocytosis is increased in PGRN deficient cells and, while early results showed an increase in exocytosis, further testing generated results that were inconclusive. Proteomic screens to identify binding partners for PGRN and granulin peptides were also carried out, but the procedures need to be optimized. Since this testing was completed, researchers have published data that confirms an increase in lysosomal exocytosis in the absence of GRN. This increase in lysosomal exocytosis should be further characterized by profiling the full spectrum of functional lysosomal enzymes that are excreted into the extracellular space and whether these enzymes negatively impact surrounding neurons. These findings could uncover a mechanistic link between GRN mutation, FTLD, and the onset of dementia.
Progranulin; Lysosome; Cellular biology; Biochemistry; Molecular biology; Frontotemporal lobar degeneration; Neurodegeneration
Lee, Siu Sylvia; Brown, William J.
Biochemistry, Molecular and Cell Biology
M.S., Biochemistry, Molecular and Cell Biology
Master of Science
dissertation or thesis