Investigation of molecular and cellular functions of TDP-43 and FUS, pathorelevant proteins in frontotemporal dementias and amyotrophic lateral sclerosis

• Applicant: Professor Dr. Philipp J. Kahle
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2010 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 162802384

TDP-43 is the neuropathologically diagnostic protein of a recently appreciated class of neurodegenerative proteopathies comprising frontotemporal dementias (FTD) and motor neuron diseases (MND) such as ALS. TDP-43 is also genetically linked to these common and incurable, deadly diseases of the central nervous system. TDP-43 is a ubiquitous nucleic acid binding protein, for which functions in transcriptional regulation and RNA processing have been described. To identify novel and pathologically relevant TDP-43 target genes, we have performed comprehensive expression profiling in TDP-43 silenced cells. We were able to confirm in cell cultures a first hit from the conventional Affymetrix microarray study, namely histone deacetylase 6 (HDAC6). Evaluation of the Exon-Arrays revealed novel splice targets of TDP-43. These novel TDP-43 target genes shall be further validated also in vivo. Functional effects on neuropathological protein transport, aggregation, degradation and toxicity and neurite functions will be investigated. Our studies on TDP-43 target genes shall provide major advances in the understanding of molecular and cellular mechanisms of the dreadful diseases FTD and ALS.

• DFG Programme: Research Grants