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Dec 11

Research Bit: Protecting the nuclear compartment with ESCRTs and Autophagy

Research Bits
The Packard Center welcomed C. Patrick Lusk from Yale University to a recent Investigator's meeting.

Meeting Date: December 11, 2020

Presenter: C. Patrick Lusk, PhD

Talk Title: Protecting the nuclear compartment with ESCRTs and Autophagy


What was the question being asked?

Work in the Lusk lab is centered around understanding how the separation between the nucleus and cytoplasm of cells is maintained and how loss of this may contribute to disease. Much of their recent work focuses on autophagy, a biological process for getting rid of damaged protein complexes within the cell. Specifically, the Lusk lab seeks to understand how autophagy helps to maintain the integrity of the nuclear envelope and other nuclear proteins.

Why is this important for ALS research?

The nuclear pore complex (NPC) is a large protein complex that spans the nuclear envelope. One of the many functions of the NPC is to control the transport of macromolecules between the nucleus and cytoplasm in a process termed nucleocytoplasmic transport (NCT). Defects in NCT and alterations to specific proteins that make up the NPC (Nups) have recently been reported in ALS and related neurodegenerative diseases. Understanding the basic cell biological mechanisms that impact the maintenance of the NPC and its functions will ultimately advance our understanding of disrupted cellular pathways that contribute to neurodegenerative disease.

What was the take-home message?

The Lusk lab has found that a specific protein involved in autophagy is able to capture specific cargo from the nuclear envelope in order to maintain nuclear integrity. Further, this process involves extensive remodeling of the nuclear envelope and involves changes to the local lipid composition. Ultimately, defects in this nuclear quality control system likely lead to cellular pathologies and dysfunction, perhaps even those observed in ALS.

How do you think the results of this study might impact future approaches to the treatment of ALS?

The work being conducted in the Lusk lab significantly advances our understanding of the biological pathways and mechanisms underlying nuclear envelope and NPC homeostasis. The molecular events Dr. Lusk and his group have uncovered may significantly contribute to the deficits in NCT and the NPC observed in ALS and related neurodegenerative diseases. Thus, understanding how these cellular events contribute to disease pathogenesis is likely to provide insights into potential new therapeutic targets. In fact, Drs. Alyssa Coyne and Jeffrey Rothstein, both at Johns Hopkins University, have been working with Dr. Lusk to understand the contribution of these pathways to NPC alterations in neurodegeneration. This collaboration has already provided novel insights into disease mechanisms and potential therapeutic strategies for mitigating disease. Moreover, this further highlights the power of the Packard Center for bringing together scientists to advance our understanding of basic and disease cell biology.

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