Interactions between TDP-43 and compartment-specific quality control machinery

• Applicant: Professor Mark S. Hipp, Ph.D.
• Subject Area: Biochemistry ; Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545039200

Our cells have sophisticated systems to keep proteins healthy and prevent them from clumping together harmfully. These quality control systems can either repair damaged proteins, dispose of ones that can't be fixed, or temporarily store them in special droplet-like compartments. Scientists understand quite well how these systems work in most parts of the cell, but we know surprisingly little about how they function in the nucleus - the cell's control center where our DNA is kept. Our research focuses on a protein called TDP-43, which has become increasingly important in medical research because its malfunction is linked to several devastating neurodegenerative diseases. What makes TDP-43 particularly interesting is its behavior: when it's in the nucleus, it usually stays healthy and functional. However, when it moves to other parts of the cell, it often clumps together in ways that damage brain cells. This difference suggests that various parts of the cell might have different ways of keeping proteins healthy. We think the nucleus has its own specialized set of helper proteins (called chaperones) that prevent TDP-43 from forming harmful clumps. These nuclear chaperones probably work differently from similar proteins in other parts of the cell. To test this idea, we will study how TDP-43 behaves differently in the nucleus compared to other parts of the cell, determine how TDP-43 interacts with different cellular machinery, and identify which specific helper proteins are responsible for protecting TDP-43 in different areas of the cell. Understanding how the nucleus naturally prevents protein clumping could be crucial for developing new treatments for brain diseases and other conditions where proteins form harmful aggregates. If we can understand how cells protect themselves, we might be able to develop new therapies that enhance these natural protective systems. This could lead to breakthroughs in treating not just one disease, but potentially several other neurodegenerative conditions where protein aggregates play a role.

• DFG Programme: Research Units
• Subproject of: FOR 5872: Chaperone-mediated regulation of the emergence of disease-causing amyloids inside biomolecular condensates