By Michelle Jaffee
New research in a fruit fly model has revealed a potential therapeutic target for ALS and frontotemporal dementia linked to TDP-43, a widely expressed nuclear protein that binds to both DNA and RNA. An international research team led by neuroscientists at Mayo Clinic in Jacksonville and the University of Florida published the study in the journal Molecular Neurodegeneration.
Diego Rincon-Limas, Ph.D., an associate professor of neurology at UF, created a fruit fly model of TDP-43 toxicity to study pathological hallmarks seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including abnormal accumulation and regulation of TDP-43. TDP-43 pathology has also been implicated in Alzheimer’s disease.
TDP-43, an essential RNA/DNA binding protein, plays multiple roles in RNA processing, and in neurodegenerative diseases it moves to the cytoplasm and forms toxic clumps, resulting in neuronal death. In collaboration with senior author Wilfried Rossoll, Ph.D., an associate professor of neuroscience at Mayo Clinic in Jacksonville, Rincon-Limas and UF assistant scientist Deepak Chhangani, Ph.D., uncovered new mechanistic insights into TDP-43 pathology.
The investigators found that glycine-rich nucleoporin Nup62, a protein generally involved in transport of cellular proteins through nuclear pores, recruits the nuclear import receptor karyopherin-b1, or KPNB1, to dissolve clumps of TDP-43 and facilitate its return to the nucleus, Rincon-Limas said. This novel finding for KPNB1 implies a potential role in conditions where toxic TDP-43 protein clumps are already formed, he said.
“This exciting result is highly relevant, because KPNB1 is mostly known for carrying nuclear proteins into the nucleus,” Rincon-Limas said. “However, the ability of KPNB1 to disaggregate TDP-43 uncovered its new unconventional role as molecular chaperone and highlighted its capability to alleviate TDP-43 toxicity and reduce neurodegeneration.”
Chhangani made the initial discovery that Ketel, the fly homologue of KPNB1, removes TDP-43 toxicity in the brain of transgenic flies. At the same time, Bilal Khalil, Ph.D., a neuroscientist at Mayo Clinic in Jacksonville, found the chaperone activity of KPNB1 against TDP-43 aggregates in cultured cells, Rincon-Limas said.
These discoveries led to a multi-year, multi-institution collaboration that used cultured neuronal cells, mouse brain slices and the fruit fly model. The authors also used human postmortem brain tissues with TDP-43 pathology to validate their findings.
The next step in this line of research is to investigate whether other nuclear import receptors are also involved in these processes and whether the findings are consistent in higher-order animal models.