Panel Discussion: What Happens Upstream of TDP-43 Misfolding? Shifting Focus from Restoring Function to Understanding Root Cause of Aggregate Pathology
- What are the earliest cellular events that trigger TDP-43 mislocalization and aggregation, and how do these upstream mechanisms vary across ALS subtypes?
- How do general protein homeostasis pathways, including nuclear import/export and stress response mechanisms, influence TDP-43 pathology?
- Which cryptic exons, epigenetic changes, or C9orf72-related mechanisms are likely contributors to disease initiation, and how should these inform target prioritization?
- How can we improve ALS model systems to better reflect the physiological context of TDP-43 misfolding and aggregate formation?
- Moving beyond restoring TDP-43 function, what strategies can drug developers adopt to intervene at the root cause of aggregate pathology?