Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes

• 成果类型: Article
• 署名作者: Rose, Kevin; Jepson, Tyler; Shukla, Sankalp; Maya-Romero, Alex; Kampmann, Martin; Xu, Ke; Hurtley, James H.
• 署名单位: University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California Berkeley; University of California System; University of California Berkeley
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13046
• DOI: 10.1073/pnas.2315690121
• 发表日期: 2024-05-28
• 关键词: chmp2b; propagation; mutations; clearance; pathology; proteins; vesicles; vps4

摘要

The prion - like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimer's disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, and the potential for coupling between the entry and nucleation mechanisms has been little explored. We found that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes. This in turn leads to lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin - 3, to the lysosomal membrane. These observations are consistent with nanoscale damage of the lysosomal membrane. Live cell imaging and STORM superresolution microscopy further show that the nucleation of cytosolic tau occurs primarily at the lysosome membrane under these conditions. These data suggest that tau seeds escape from lysosomes via nanoscale damage rather than wholesale rupture and that nucleation of cytosolic tau commences as soon as tau fibril ends emerge from the lysosomal membrane.