Microaggrephagy: an ESCRT-I-PTPN23-dependent pathway for MAPT/tau aggregate clearance

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• Clearance mechanisms for ubiquitinated protein aggregates, crucial in neurodegenerative diseases like those involving MAPT/tau, are not fully understood.
• The specific role of microautophagy in degrading these aggregates remains largely unexplored.

Purpose of the Study:

• To identify key mediators involved in the microautophagy-dependent clearance of ubiquitinated protein aggregates.
• To elucidate the molecular mechanisms underlying this novel degradation pathway.

Main Methods:

• Conducted an unbiased, genome-wide CRISPR knockout screen in cells expressing MAPT/tau aggregates.
• Utilized biochemical assays to investigate protein interactions and pathway components.

Main Results:

• Identified the ESCRT-I complex and PTPN23 as essential for clearing MAPT/tau aggregates via microautophagy, a process termed "microaggrephagy."
• Demonstrated that microaggrephagy functions independently of macroautophagy and chaperone-mediated autophagy.
• Uncovered that TSG101 recognizes ubiquitinated aggregates, with PTPN23 bridging ESCRT-I and ESCRT-III.
• Showed that a disease-associated UBAP1 mutation impairs MAPT/tau clearance by disrupting the UBAP1-PTPN23 interaction.

Conclusions:

• Established "microaggrephagy" as a distinct cellular pathway for degrading pathological protein aggregates.
• Provided a molecular framework for microaggrephagy, highlighting the roles of ESCRT-I, PTPN23, and TSG101.
• Linked dysfunction of this pathway to neurodegenerative pathogenesis and suggested it as a potential therapeutic target for proteinopathies.