Ana Bajc Česnik, Boris Rogelj
Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
Amyotrophic lateral sclerosis (ALS) is an adult onset disorder, which is phenotypically characterized by progressive muscle weakness and neuropathologically by degeneration of upper and lower motor neurons and frontal cortex. TDP-43 protein was identified as a major component of the ubiquitinated cytoplasmic inclusions in 97 % of all ALS cases, whether sporadic or familial. Structurally, TDP-43 belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family and consists of two RNA recognition motif domains (RRM-1 and RRM-2), nuclear localization signal (NLS), nuclear export signal (NES) and a Gly-rich C-terminal region, which mediates protein-protein interactions. In healthy individuals, TDP-43 is localized predominantly in the nucleus but constantly shuttles between the nucleus and the cytoplasm. In the affected cells, it is cleared from the nucleus and ubiquitinated, hyperphosphorylated and cleaved into aggregation-prone C-terminal fragments forms pathologic inclusions in the cytoplasm. Most of the mutations identified in ALS cases are located in the highly conserved region of the C-terminus of the TDP-43, which was shown to have prion-like properties. In recent years a new prion paradigm has emerged, which suggests that the misfolded proteins associated with neuronal deterioration can spread the pathology in a “prion-like” manner and thus facilitate the disease progression. Our aim is to determine the mechanisms, which allow TDP-43 spread between mammalian cells in the culture.
Keywords: ALS, TDP-43, prion-like propagation