Arisla | The research

Active project: ALSMNDTDP-43

ALSMNDTDP-43.

Molecular characterization of TDP-43 function in vivo and the mechanisms that lead to motoneuron disease in Drosophila models of ALS.

The nuclear factor TDP-43 is an evolutionary conserved RNA binding protein that plays different roles in several cellular processes such as mRNA transcription, splicing, stability, and transport. Recently, TDP-43 has also been found as the major protein component of the intracellular inclusions occurring in the neuronal tissues of patients affected by a series of neurodegenerative diseases. In affected neurons, TDP-43 is abnormally mislocalized in the cytoplasm, ubiquitinated, hyperphosphorylated, and cleaved to generate C-terminal fragments (CTFs). In addition, TDP-43 mutations have been identified in familial and sporadic cases of amyotrophic lateral sclerosis (ALS), suggesting that all these changes may play a pivotal role in neurodegeneration as they may result in the loss of proper TDP-43 function in the nucleus (loss-of-function effects) and/or the release of potentially toxic C-terminal fragments in the cytoplasm (gain-of-function effects). At the moment neither the physiological role of TDP-43 in vivo nor the mechanisms that may lead to neurodegeneration are known.

To address these issues, we have generated different Drosophila animal models of TDP-43 function by deleting the Drosophila TDP-43 endogenous gene TBPH and creating transgenic flies expressing the human protein. Our Drosophila models show that lack of TDP-43 function, without the formation of protein aggregates, produces a paralytic phenotype with altered locomotive behaviours, reduced life span and atrophic presynaptic terminals at the neuromuscular junctions. Most importantly, the expression of human TDP-43 in motoneurons was able to recover these structural defects, demonstrating the functional equivalence between these proteins in such evolutionary distant species. These results suggest that the TBPH mutant flies represents an extraordinary animal model that closely mimics ALS pathology in the nervous system and demonstrate that TDP-43 proteinopathies are also consistent with a loss-of-function scenario.

The following project application aims to provide an in-depth study of the biological role played by TDP-43 in vivo, especially focusing on the identification of the target molecules and mechanisms regulated by these genes. Successful candidates will then be used in a "drug discovery” approach paving the way for prospective pharmaceutical approaches.

Research Team:

Principal Investigator:

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Fabian Feiguin

International Center for Genetic Engineering and Biotechnology (ICGEB)

E mail feiguin@icgeb.org

Curriculum and References

Staff scientists

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Collaborators directly involved in the project:
Chiara Appocher, PhD Student.
Giulia Romano, PhD Student.
Giuseppe Tato', PhD Student.
Giulia Rampone, Undergraduate Student.

Partner 1:

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