Genome-wide ribosome profiling reveals a translational enhancer function for TDP-43 in cellular models of neurodegenerative disease ; Genomweites Ribosome Profiling enthüllt eine translationale Verstärkerfunktion von TDP-43 in zellulären Modellen neurodegenerativer Erkrankungen

Altered function of the RNA-binding protein Transactive Response (TAR) DNABinding Protein 43 (TDP-43) is implicated in the neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). TDP-43 mutations are detected in many patients and the protein is one of the major components of the ubiquitinated inclusions that are characteristic pathological features of these diseases. During disease, the level of cytoplasmic TDP-43 is significantly increased in diseased neurons. This increase in cytoplasmic TDP-43 levels suggests a potentially important role in this cellular compartment. In spite of significant research, it remains unclear how altered TDP-43 function causes disease. Cell and animal models support a key role in disease for altered regulation of cellular RNAs in motor neurons by TDP-43, including effects on transcription, splicing and stability. Proteomic studies have revealed that TDP-43 interacts with many cytoplasmic proteins almost all of which are involved in translation. Intriguingly, many of these interacting proteins are also found in stress granules, dynamic cellular ribonucleoprotein structures believed to be important for translational control. Recent work has also implicated TDP-43 in transport of mRNAs in neurons, a process that is typically linked to translational control. To date, only a handful of TDP-43 translational targets have been identified. Taken together, these observations support the idea that TDP-43 might regulate translation in the cytoplasm in healthy neurons and that altered translational control by TDP-43 could contribute to disease. However, there is little evidence for this idea to date. Although previous studies have revealed TDP-43’s direct RNA targets and function in many aspects of mRNA metabolism, it remains unresolved which effects on gene expression are the key drivers of disease. Here, I used ribosome profiling of motor neuron cell lines and primary cortical neurons to identify mRNAs whose translation is altered by a TDP-43 patient ...