NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• C9orf72 gene expansions are a leading cause of ALS and FTLD.
• TDP-43 proteinopathy and impaired nucleocytoplasmic transport are key features.
• The role of FG nucleoporins (FG nups) in TDP-43 pathology is unclear.

Purpose of the Study:

• Investigate the link between FG nups and TDP-43 pathology in C9-ALS/FTLD.
• Determine the role of NUP62 in the disease mechanism.

Main Methods:

• Utilized induced pluripotent stem cell (iPSC)-derived neurons from C9-ALS/FTLD patients.
• Examined NUP62 and TDP-43 localization and interactions.
• Analyzed postmortem central nervous system (CNS) tissue.

Main Results:

• Observed nuclear depletion and cytoplasmic mislocalization of NUP62 in C9-ALS/FTLD neurons.
• Found that poly-glycine arginine (GR) dipeptide repeat protein (DPR) accumulation recruits NUP62 and TDP-43 to cytoplasmic RNA granules.
• Demonstrated that cytoplasmic NUP62 and TDP-43 interactions increase their insolubility, forming inclusions found in patient tissues.

Conclusions:

• NUP62 cytoplasmic mislocalization is a significant factor in TDP-43 proteinopathy in ALS/FTLD.
• NUP62-TDP-43 inclusions are a potential hallmark of C9orf72 and sporadic ALS/FTLD.