Abstract
TAR DNA binding protein 43 KD (TDP-43) is an essential gene that regulates gene transcription, mRNA splicing and stability. In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two fatal neurodegenerative diseases, TDP-43 is fragmented, generating multiple fragments that include the C-terminal fragment of ∼25 KD. The role of these fragments in the pathogenesis of ALS and FTD is not clear. Here we investigated the aggregation propensity in various polypeptide regions of TDP-43 in mammalian cells and the effect of these fragments on cultured neurons. By expressing the full length and various TDP-43 fragments in motor neuron-derived NSC-34 cells and primary neurons, we found that both N- and C-terminal fragments of TDP-43 are prone to aggregate and the C-terminal end of RRM2 region is required, though not sufficient, for aggregation. The aggregation of the TDP-43 fragments can drive co-aggregation with the full-length TDP-43, consequently reducing the nuclear TDP-43. In addition, the TDP-43 fragments can impair neurite growth during neuronal differentiation. Importantly, overexpression of the full-length TDP-43 rescues the neurite growth phenotype whereas knockdown of the endogenous TDP-43 reproduces this phenotype. These results suggest that TDP-43 fragments, particularly the pathologically relevant C-terminal fragments, can impair neuronal differentiation by dominant-negatively interfering with the function of the full length TDP-43, thus playing a role in pathogenesis in ALS and FTD.
Highlights
TAR DNA binding protein-43 (TDP-43) has been identified as a major component of the ubiquitin-positive protein inclusions in neurons and glia in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) as well as several other neurodegenerative disorders [1]
To further understand the aggregation propensity of TDP-43 and the role of TDP-43 fragments in pathogenesis, we engineered a series of TDP-43 truncation fragments and expressed these fragments in cultured neurons. We found that both the C-terminal and the N-terminal fragments of TDP-43 can form aggregates as long as they contain the C-terminal end of the RRM2, which is necessary but by itself is insufficient for aggregation
Our data show that both the C-terminal and the N-terminal fragments of TDP-43 can form aggregates in mammalian cells as long as they contain the C-terminal end of the RRM2 (Fig. 1, 2, Table 1)
Summary
TAR DNA binding protein-43 (TDP-43) has been identified as a major component of the ubiquitin-positive protein inclusions in neurons and glia in ALS, FTD as well as several other neurodegenerative disorders [1]. TDP-43 is present in granular structures in the cytoplasm and may be involved in RNA transport and stress response [6,16,17] In both ALS and FTD, TDP-43 is fragmented, resulting in lower molecular weight C-terminal fragments of ,35 to ,25 KD [18]. The C-terminal fragments are prominent in the inclusions in FTD brains and in the insoluble protein fractions from the affected CNS areas of ALS and FTD [18,19] These fragments are phosphorylated at serine 409 and 410 and antibodies against this phosphorylation epitope is used as an excellent marker for visualizing TDP-43 inclusions [20]. The pathological role of the C-terminal fragments remains unclear
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