Lysosome turnover in health, aging and disease (360G-Wellcome-212216_Z_18_Z)

Lysosome dysfunction is implicated in lysosomal storage diseases, and multiple age-related neurodegenerative diseases, including Parkinson’s, Alzheimer’s and age-related macular disease. Lysosomes are signalling organelles central to maintaining cellular homeostasis. Nutrient sensing on the lysosome can lead to nuclear translocation of the transcription factor, TFEB, and lysosomal gene transcription. However, it remains unclear how newly synthesised lysosomal proteins are packaged into new lysosomes and how old/damaged lysosomes are cleared. We recently established models of lysosomal aging/dysfunction in retinal pigment epithelial cells, taking advantage of their huge degradative burden, and identified conditions that upregulate lysosome biogenesis/activity. We propose to identify the trafficking steps and molecular machinery underlying lysosome biogenesis and test the relative contributions of lysosome exocytosis and lysophagy (lysosome autophagy) to cellular clearance of aged/damaged lysosomes. Our ultimate goal is to exploit these mechanisms to promote damaged lysosome clearance or rejuvenation and/or promote lysosome biogenesis for the treatment of diseases where lysosome activity is compromised. Treatment efficacy in upregulating lysosome activity, whilst readily measurable in culture, is difficult to assess in vivo. We will establish a molecular signature of aged/damaged lysosomes in cultured RPE that can be used to identify damaged lysosomes in aged/diseased retinae.