TDP-43 aggregates in Amyotrophic Lateral Sclerosis (ALS): composition and biological effects

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder that leads over time to a more and more severe loss of motor function. The reason for this loss of motor function is that the motor neurons in the spinal cord as well as the primary motor neurons in the precentral gyrus degenerate. Although other proteins can also represent pathological correlates of ALS, most frequently aggregates of TDP43 are found in cases of sporadic but also familial ALS. This project is focusing on the mechanisms of motor neuron and axonal degeneration in relation to TDP-43 pathology. We are assessing the activation of distinct cell death mechanisms (i.e. necroptosis, pyroptosis) in post-mortem human brain and spinal cord tissue, as well as in a transgenic mouse model for ALS. Furthermore, we are investigating the role of tubulin alterations in ALS using human post-mortem tissue as well as in vivo experiments in zebrafish. This will help us to better understand the different pathways involved in ALS pathogenesis, and to eventually develop treatments that can interfere with motor neuron and axonal degeneration in ALS.