Researchers from Emory University School of Medicine (GA, USA) and Mayo Clinic (FL, USA) have identified a protein that appears to aggregate and disrupt cellular trafficking systems in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Most cases of ALS are sporadic, whilst only a minority are solely caused by inherited mutations in the C9orf72 gene. Previously, this mutation was thought to influence the protein in question, TAR DNA binding protein-43 (TDP-43); however, this research suggests the protein is itself an independent perpetrator of disease pathology.
TDP-43 is normally located in the nucleus, but in neurones affected by ALS, it truncates and forms aggregates in the cytoplasm. These aggregates have traditionally been difficult to study due to their insolubility, but in this study the team utilized novel methods to visualize them.
Proximity-dependent biotin identification was used to tag TDP-43 and track its intracellular movements. This revealed that in neurones where TDP-43 aggregates, gatekeeper proteins of the nuclear pore cluster as well. Such proteins are crucial for transporting substances such as RNA in and out of the nucleus, hence their accumulation, which alters the shape of the nuclear pore, disrupts the normal trafficking system.
The researchers also observed clusters of nuclear pore proteins in post-mortem examinations of brain tissue from ALS and FTD patients. Interestingly, these were visible in both sporadic and genetic cases of the disease, suggesting that TDP-43 pathology is not reliant on the mutation of C9orf72 to cause pathology.
This research brings new hope of therapeutic treatments for ALS and FTD, as a drug to regulate nuclear transporter routes may hold promise. The team demonstrated that KPT-335 or verdinexor, produced by Karyopharm Therapeutics (MA, USA), inhibited nuclear export, which may compensate for excess TDP-43 levels and help to control disrupted intracellular trafficking. Similar drugs have also seen encouraging results in animal models and are now headed for clinical trials.
Sources: Chou CC, Zhang Y, Umoh ME et al. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat. Neurosci. doi:10.1038/s41593-017-0047-3. (2018) (Epub ahead of print);