Progranulin Dosage and Modulation of Lysosomal pH: Rotating During a Pandemic by Katerina Rademacher

Katerina Rademacher

UC San Francisco | Kayla & Jamie Grodsky Memorial

Failures in autophagy are common features across multiple neurodegenerative diseases including frontotemporal lobar degeneration (FTLD), Alzheimer’s disease, and Parkinson’s disease. Lysosomal enzymes have tight optimal pH ranges, and even small shifts in lysosomal pH can severely disrupt lysosomal function. Progranulin (PGRN) is a cysteine-rich lysosomal protein and PGRN deficiency may promote neurodegeneration by altering lysosomal pH.

ABSTRACT

Neurodegenerative diseases are becoming increasingly prevalent as the global population ages. Complications in autophagy are common features across multiple neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD), Alzheimer’s disease, and Parkinson’s disease which strongly implicates a role for autophagy in disease pathogenesis. Lysosomal enzymes have tight optimal pH ranges, and even small shifts in lysosomal pH can severely disrupt lysosomal function. In general, lysosomal pH is maintained at 4.5. Progranulin (PGRN) is a cysteine-rich lysosomal protein that can be cleaved into 7.5 individual granulins (GRANs). Homozygous Pgrn mutations (functional nulls) result in ceroid neuronal lipofuscinosis, a lysosomal storage disease, while Pgrn haploinsufficiency has been linked to a behavioral variant of FTLD with TDP-43 inclusions. We hypothesize that an imbalance between the relative abundance of progranulin and individual granulins promotes neurodegeneration by altering lysosomal pH. In this model, when Pgrn is haploinsufficient, lysosomal proteases work to cleave a smaller pool of fulllength PGRN, resulting in an imbalance of full-length PGRN to individual granulins. For this rotation project I used SH-SY5Y cells that express a lysosomal pH sensor (FIRE-pHLy) to show that changes in PGRN dosage can alter lysosomal pH.

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