SYNDYS-ALS/FTD

In the brain and spinal cord, there are about 100 billion nerve cells, or neurons, that enable us to think, remember, see, hear, speak, feel... and move. Neurons talk to each other at connections called synapses. Motor neurons that control our movements connect to muscles at neuromuscular junctions.

Communication between neurons and between motor neurons and muscle is called neurotransmission. Neurological conditions such as dementia or motor neuron disease start when communication at synapses or neuromuscular junctions becomes disrupted. When the communication is disrupted for too long, synapses and neuromuscular junctions break down, and finally neurons die off and are lost forever.

In this project we want to investigate what causes synapses to malfunction and disappear in two related neurological diseases, namely amyotrophic lateral sclerosis (ALS), which is the most common form of motor neuron disease, and a form of dementia called frontotemporal dementia (FTD). ALS and FTD overlap genetically, pathologically, and clinically.

Familial forms of both diseases can be caused by mutations in a number of genes including the TARDBP gene (encoding for TDP-43), and the C9orf72 gene. Mutations in the C9orf72 gene are the most common genetic cause of both ALS and FTD. The mechanisms behind ALS and FTD are varied and not well understood, but the symptoms of these diseases ultimately are the result of a failure in neurotransmission.

Our previous research found that losing the C9orf72 protein reduces neurotransmission, which disrupts neuron activity and brain function in a manner similar to what happens in ALS/FTD patients. Similarly, defective TDP-43, which is present in nearly all ALS/FTD cases, also directly affects synapses. Evidence from our lab and others points to a specific part of the synapse called the presynapse as the main site of damage in ALS/FTD.

The goal of this project is to understand how the presynapse is disrupted in ALS/FTD and how this causes the breakdown in communication between neuron that we see in patients. Discovering this could lead to new therapies.