Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already
A new $4.8 million grant will support researchers from Indiana University School of Medicine and the Medical Research Council Laboratory of Molecular Biology to study how human neurodegenerative diseases are affected by the misfolding of the protein TDP-43.
Scientists at the University of Zurich have developed an innovative neural cell culture model, shedding light on the intricate mechanisms underlying neurodegeneration.
Neuroscientists at Macquarie University in Australia have developed a single-dose genetic medicine that has been proven to halt the progression of both ALS and frontotemporal dementia (FTD) in mice – and may even offer the potential to reverse some of the effects of the fatal diseases.
Scientists from the Rush University Medical Center in Chicago, United States, investigated whether brain pathology related to dementia, such as cerebrovascular pathology, phosphorylated tau fibril tangles, and β-amyloid accumulation, modify the association between healthy lifestyle choices and cognition during the later years in life.