The role of TDP-43 dysfunction in motor neurone disease
Lead Research Organisation:
King's College London
Department Name: Neuroscience
Abstract
We investigate how motor neurones degenerate in a fruitfly model of Motor Neurone Disease. This can directly guide clinical research and advance the development of novel therapeutic treatments.
Motor Neurone Diseases, such as Amyotrophic Lateral Sclerosis, are fatal neurological disorders characterized by the loss of muscle innervation. There is currently no treatment for these diseases and little is known about the causes.
Recently, the TDP-43 protein was identified as the major component of abnormal aggregates found in affected nerve cells of Motor Neurone Disease patients. However, the function of TDP-43 in the nervous system is not known, nor is it clear whether these aggregates play a direct role in disease formation.
The fruitfly Drosophila is an ideal model system to study neurological disorders such as Motor Neuron Disease. Although the fly has a less complex central nervous system than humans, the major building blocks are comparable, especially motor neurons and muscle innervation.
Drosophila encodes a TDP-43 protein that is similar to the human protein affected in Motor Neuron Disease. By studying the function of TDP-43 in the fruitfly, we can learn about the role of TDP-43 in motor neurons, muscle innervation, and disease formation.
Motor Neurone Diseases, such as Amyotrophic Lateral Sclerosis, are fatal neurological disorders characterized by the loss of muscle innervation. There is currently no treatment for these diseases and little is known about the causes.
Recently, the TDP-43 protein was identified as the major component of abnormal aggregates found in affected nerve cells of Motor Neurone Disease patients. However, the function of TDP-43 in the nervous system is not known, nor is it clear whether these aggregates play a direct role in disease formation.
The fruitfly Drosophila is an ideal model system to study neurological disorders such as Motor Neuron Disease. Although the fly has a less complex central nervous system than humans, the major building blocks are comparable, especially motor neurons and muscle innervation.
Drosophila encodes a TDP-43 protein that is similar to the human protein affected in Motor Neuron Disease. By studying the function of TDP-43 in the fruitfly, we can learn about the role of TDP-43 in motor neurons, muscle innervation, and disease formation.
Technical Summary
Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS), cause progressive paralysis and are typically fatal within 2-5 years of symptom onset. Every year, 1,200 people die of MND in the UK and more than 100,000 patients are affected globally. There is no treatment that significantly retards disease progression and many patients seek physician-assisted suicide. MND involves selective degeneration of upper and lower motor neurons in the brain and spinal cord. Approximately, 90% of MND cases are sporadic whereas 10% of cases are familial. Although familial cases of MND are defined either by heredity or by testing positive for a known genetic mutation associated with the disease, little is known about the aetiology of the motor neuron dysfunction. Recently, the TAR DNA binding protein-43 (TDP-43) was identified as the major disease protein in neuronal inclusions in ALS and Frontotemporal Lobar Degeneration with ubiquitin-positive inclusions (FTLD-U). However, it is not clear whether neuronal inclusions play a direct role in disease pathogenesis or whether they represent a cellular defence mechanism (1-3). My hypothesis is that aberrant function of TDP-43 plays an aetiological role in the early stages of MND. This hypothesis predicts that TDP-43 function is abnormal in the preclinical phase of the disease and suggests that manipulation of TDP-43 function in patients with MND could modify the course of the disease. The key issues would be addressed most rapidly in a model system that i) has a homologue of TDP-43 expressed in neurons that could be manipulated experimentally and ii) permits studies of motor behaviour throughout a, preferably short, life cycle to follow the progression of the disease. These requirements are fulfilled by the fruit fly, Drosophila melanogaster, which has been used to study other human neurodegenerative diseases. Hence, I propose to develop a model of MND in Drosophila. The fly model would enable me to investigate the cellular mechanisms that result in MND and permit manipulations that alter the course of the disease. My long-term goal is to use the fly model to develop new treatments that target the early stages of MND.
