TDP-43 regulates hundreds of transcripts. Do a small number of these target genes account for disease pathogenesis and progression, or are TDP-43 proteinopathies the result of many modest molecular ‘paper cuts’ collectively summing to major dysfunctions?
Can restoration of a small number of TDP-43 target RNAs (e.g., STMN2) serve as a clinical strategy for TDP-43 proteinopathies, or do therapeutic approaches need to focus on pathways upstream of TDP-43 to restore a broader set of transcripts?
More than 50 mutations associated with disease have been identified in TARDBP . What are the consequences of these mutations on TDP-43 function, and do they lead to distinct or common defects?
The ability of TDP-43 to phase separate into biomolecular condensates is well established, but how is this process regulated in response to cellular stresses? Are there signal transduction cascades that regulate the ability of TDP-43 to specifically respond to these insults? If so, what are they?
TDP-43 pathology has also been observed in astrocytes. Does TDP-43 pathology in non-neuronal cell types also lead to significant alterations in RNA metabolism? Does pathology in non-neuronal cells contribute to disease onset or progression?
Reduced STMN2 expression has been observed in other TDP-43 proteinopathies. Is the mechanism behind reduced STMN2 expression also the consequence of premature polyadenylation and inclusion of a cryptic exon, or is it the result of neuronal loss?
子夜星河 