Dysregulation of RNA processing as a driver of motor neuron dysfunction in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) (also known as motor neuron disease), is caused by a loss of motor nerves or neurons. These motor nerves carry signals from the brain and spinal cord to the peripheral muscles allowing everyday movements. Loss of motor nerves in these patients leads to progressive muscle paralysis and eventual death due to failure of muscles that allow us to breath. About ~10-15% of ALS cases have a family history and specific defects, called mutations, in several genes with diverse functions are known to cause ALS. However, the processes driving motor neuron loss are poorly understood. Though the cause of ALS is unknown, many of the nerves affected in these patients show a common feature. This feature involves incorrect migration of a protein called TDP43 from within the nucleus of a cell, outside into its cytoplasm. The nucleus is the command centre of the cell and contains our DNA with specific instructions on how to make different proteins, the workhorses in a cell. The cytoplasm is the gel-like liquid within the cell that contains the nucleus and has the machinery to make proteins. Each of the nucleus and the cytoplasm have defined roles that are dependent on precise availability of specific proteins. Thus, any change in the proteins' locations will interfere with the normal activity of nerve cells resulting in their death. Relocation, also called mislocalization, of TDP43 protein from the nucleus to the cytoplasm perturbs the normal function of the nerve cells causing them to die. We have developed a new way to trigger TDP43 protein mislocalization in human nerve cells in a dish. This will allow us to look at the consequences of this relocation in detail.

With the advent of a new stem cell technology called reprogramming, skin or blood cells from patients can be converted into an embryonic state. These reprogrammed cells are called induced pluripotent stem cells (iPSC) and have the potential to be converted to any type of cell in the body....