image: In HGPS cells, progerin can be expelled from the nucleus into the cytoplasm via nuclear envelope budding and degraded through lysosomes. However, lysosome defects, which impair progerin clearance, occur in progeria cells. PMA or Torin 1 treatment promotes the nuclear translocation of TFEB, activates lysosome biogenesis and progerin clearance in HGPS cells, and accordingly alleviates senescence phenotypes, including DNA damage, cell cycle arrest, low proliferation ability and SASP. (PMA, phorbol 12-myristate 13-acetate; SASP, senescence-associated secretory phenotype.)
Credit: ©Science China Press
Hutchinson-Gilford progeria syndrome (HGPS) is a rare progeroid disorder, featured with premature skin wrinkling, lack of skin elasticity, absence of subcutaneous fat, alopecia, atherosclerosis and insulin resistance (https://rarediseases.info.nih.gov/diseases/7467/progeria). Previous studies have showed that approximately 90% of HGPS cases are caused by progerin. Progerin displays dominant-negative behavior and causes a series of abnormalities, including nuclear envelope (NE) lobulation and budding, DNA damage increase, telomere loss, cell cycle arrest and low proliferation ability. More and more studies report that progerin is also detected in physiological aging and chronic kidney disease (CKD). Therefore, advances in progerin clearance provide powerful potential for the treatment of HGPS, CKD and aging-related diseases.
Professor Chuanmao Zhang and his group, from Peking University and Kunming University of Science and Technology, have been devoted to dissecting the underlying mechanism of progeria and aging. Recently, they publish online a study in the journal Science China Life Sciences, elucidate the lysosome-mediated clearance pathway of progerin, unveil lysosome defects in HGPS, and further demonstrate that activation of lysosome biogenesis counteracts lysosome defects and promotes progerin clearance and mitigates cellular senescence. The findings underscore the pivotal role of lysosomes in progerin clearance, providing novel insights for therapeutic interventions in HGPS, CKD and age-related disorders.
Through immunofluorescence, live-cell imaging and biochemical analyses, they discovered that the NE-localized progerin could be transported to the cytoplasm via NE budding and subsequently degraded through the autophagy-lysosome pathway. Further investigation revealed that progerin translocated to the cytoplasm was not efficiently cleared and accumulated in the cytoplasm. To elucidate the underlying molecular mechanisms, RNA sequencing was performed on primary cells from two HGPS patients, which demonstrated significant downregulation of genes associated with lysosomal function in both patients. Lysosome defects in HGPS were further validated by reverse transcription quantitative PCR (RT-qPCR), immunofluorescence and biochemical assays.
Subsequently, they explored whether counteracting lysosome defects could enhance progerin clearance and mitigate cellular senescence. Lysosome biogenesis was activated through two distinct approaches: stimulation of protein kinase C (PKC) or inhibition of mammalian target of rapamycin complex 1 (mTORC1). The results indicated that activation of lysosome biogenesis markedly counteracted lysosome defects, accelerated progerin clearance, and alleviated key senescence-associated phenotypes, including DNA damage, cell cycle arrest, and diminished proliferative capacity.
In conclusion, this study not only delineates the critical role of lysosomes in progerin clearance but also highlights the anti-aging potential of targeting lysosome biogenesis, offering innovative therapeutic avenues for HGPS and other age-related disorders.
Journal
Science China Life Sciences