TDP-43 and its role in neurodegeneration

Ubiquitinated TDP-43 (TAR DNA Binding Protein) inclusions are a hallmark of ALS (amyotrophic lateral sclerosis) and FTLD-TDP-43 (frontotemporal lobar degeneration with ubiquitin inclusions). These diseases share a similar pathology of cytoplasmic ubiquitinated TDP-43 inclusions, which contain C-terminally truncated TDP-43. Recent studies have shown that TDP-43 binds to more than 30% of the mouse RNA transcriptome suggesting a very complex nature of TDP-43 functions, making it difficult to understand mechanisms underlying toxicity. Proposed mechanisms of TDP-43 toxicity suggest presence of both a) loss-of-normal function of TDP-43, which may be due to formation of aberrant forms of TDP-43 or being sequestered in aggregates, and, b) gain-of-toxic function of aberrant TDP-43 with unique protein-protein or protein-RNA interactions along with defective clearance mechanisms that may play a major role in disease pathogenesis. However, the exact molecular mechanism by which this pathology is carried out is unknown. Therefore, we hypothesize that aberrant forms of TDP-43 are more prone to post-translational modifications like hyperphosphorylation and aggregation, thus affecting the structure/function of TDP-43 leading to toxicity.
We utilized Drosophila melanogaster as the animal model to study TDP-43 pathology. Our results show that over-expression of wild-type human TDP-43 in a tissue specific manner is toxic, and mutant forms of TDP-43 are more prone to aggregation and cytotoxicity. In particular, Q331K is more prone to form high molecular weight species and its toxicity correlates to the level of high molecular weight species of TDP-43. In addition, Drosophila homologue of Casein Kinase 1- (CK1-), dbt, is a “specific kinase” that phosphorylates “disease-specific site S409/410” and in particular phosphorylation of S409/410 by dbt correlates to severe toxic eye phenotype and partial lethality in ALS mutant Q331K. Our results suggest that hyperphosphorylation of ALS mutant TDP-43Q331K may change the structure of TDP-43 and increases the formation of soluble oligomeric species which may further lead to toxicity directly by forming novel protein-protein interactions or by impairing clearance mechanisms leading to disease pathogenesis. Therefore, we conclude that our findings bring new evidence to the understanding of TDP-43-mediated toxicity leading to neurodegeneration and may aid in the development of pharmacological therapy for human disease.