Functional consequences of mutations in the TARDBP gene associated with amyotrophic lateral sclerosis

Current Research Project

Title / Titel: Functional consequences of mutations in the TARDBP gene associated with amyotrophic lateral sclerosis

Summary / Zusammenfassung: TDP-43 is the major disease protein in two devastating and fatal neurodegenerative
diseases: Frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis
(ALS). FTLD is the second most common cause of dementia in patients under the age of 65
years, while ALS is the most common neuromuscular disorder leading to progressive muscle
weakness and death within 3-5 years. As we have shown previously, both diseases are
characterized by the abnormal accumulation of hyperphosphorylated and truncated TDP-43
species in neurons and glial cells. However, the mechanisms leading to TDP-43 accumulation and cell death are unknown. The very recent identification of mutations in the TARDBP gene encoding for TDP-43 in familial forms of ALS provides strong evidence that TDP-43 malfunction is directly involved in the pathogenesis and neurodegenerative process in these conditions. We will determine whether TARDBP mutations affect proposed functions of TDP-43 such as transcription regulation and/or mRNA processing. Finally, we will study the biochemical properties of mutated TDP-43. In-vitro and cell culture analysis will be complemented by transgenic mouse models overexpressing TDP-43 mutations. We expect that elucidating the functional consequences of ALS-associated TARDBP mutations will provide important insights into the disease mechanisms underlying ALS and FTLD-U.

Keywords / Suchbegriffe: TDP-43, dementia, neurodegeneration, amyotrophic lateral sclerosis

Project Leadership and Contacts / Projektleitung und Kontakte

Prof. Dr. Manuela Neumann, MD (Project Leader)