Poly(ADP-ribose) Engages the TDP-43 Nuclear-Localization Sequence to Regulate Granulo-Filamentous Aggregation

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• TAR DNA-binding protein of 43 kDa (TDP-43) aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).
• Disease-associated TDP-43 is N-terminally truncated, with deposits mainly comprising the C-terminal prion-like domain (PrLD).
• The PrLD is inherently aggregation-prone and hypothesized to drive TDP-43 aggregation.

Purpose of the Study:

• To investigate the role of the N-terminal region in TDP-43 aggregation.
• To determine the effect of poly(ADP-ribose) (PAR) on TDP-43 aggregation.
• To elucidate how N-terminal truncation influences TDP-43 aggregation pathways.

Main Methods:

• In vitro studies of TDP-43 aggregation kinetics.
• Analysis of TDP-43 aggregation in the presence of poly(ADP-ribose) (PAR).
• Investigation of TDP-43 variants with progressive N-terminal truncations.

Main Results:

• The N-terminal region of TDP-43 is critical for rapid granulo-filamentous aggregation.
• Poly(ADP-ribose) (PAR) inhibits TDP-43 aggregation by binding to motifs within the nuclear-localization sequence.
• Progressive N-terminal truncation decelerates aggregation and promotes thread-like fibril formation.

Conclusions:

• TDP-43's N-terminal region promotes rapid granulo-filamentous aggregation.
• PAR binding antagonizes TDP-43 aggregation, influencing aggregation pathways.
• N-terminal truncation and PAR interaction modulate TDP-43 aggregation complexity.