Investigating the role of TDP43 dysregulation in driving neuronal degeneration in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition that causes the loss of motor neurons in the brain and spinal cord. Some ALS cases are familial, but around 90-95% are sporadic and patients usually die within 3-5 years due to paralysis. There is no cure for ALS and the main existing treatment lacks effectiveness, thus new therapies are required. To achieve this, creating a disease model is an effective way to try and uncover potential targets. ALS and other neurodegenerative conditions display dysregulations in a RNA binding protein called TDP43 and are collectively known as TDP43 proteinopathies. In these conditions TDP43 can be mislocalized to the cytoplasm and sparse in the nucleus, where it is normally abundant in healthy individuals. TDP43 is involved in regulating splicing and plays a role in microRNA biogenesis. This study uses a method of TDP43 mislocalization as well as independent knockdown to create a disease model to observe the effects of TDP43 dysregulation in differentiated human neurons. This study shows that TDP43 mislocalization is toxic to cell phenotype and causes microRNA downregulation, while TDP43 knockdown and nuclear absence is what dysregulates splicing. Therefore, these results indicate that TDP43 plays a role in neuron death and ALS pathology and targeting this protein, or its dysregulated miRNAs may be beneficial to develop therapies for ALS and other TDP43 proteinopathies. Hence, future experiments can combine the methods from this study to make an accurate in-vitro model of TDP43 pathology as observed in patients and used to investigate miRNAs, splicing defects and possible new therapeutic targets for TDP43 dysregulation in ALS and other neurodegenerative diseases.