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Sep 13
2019

Research Bit: Poly-GA aggregates induce synaptic defects in the absence of neuronal death

Research Bits
The Packard Center welcomed Brigid Jensen (from the labs of Dr. Davide Trotti and Piera Pasinelli at Thomas Jefferson University) to a recent Investigator's Meeting.

Meeting Date: 13 September 2019

Presenter: Brigid Jensen (from the labs of Dr. Davide Trotti and Piera Pasinelli at Thomas Jefferson University) 

Talk Title:  Poly-GA aggregates induce synaptic defects in the absence of neuronal death

 

What was the question being asked?

Since ALS is a disease the eventually leads to the death of motor neurons, many labs focus their research on how ALS-linked mutations lead to neuronal death. This work is unique in its attempt to understand how one particular toxic molecule (poly-GA) produced due to the C9orf72 ALS mutation, can lead to changes in the function of affected neurons without necessarily killing them. Specifically, the investigation was focused on how synapses (the connections between motor neurons and muscles) are weakened due to the presence of this poly-GA molecule.

Why is this important for ALS research?

Preventing the death of diseased neurons is the foremost goal of ALS research. However, keeping the neurons alive is only half the battle. Indeed, the work mentioned here provides insight into how ALS affects neurons that are not already headed towards death. Learning how to keep these cells functional, once death is prevented, will be important to ensure that ALS patients retain normal control of their muscles.

What was the take-home message?

The most important finding was that the presence of poly-GA in neurons leads to reduced function of the neurons at the synapse. Specifically, a protein involved in the communication between motor neurons and muscles, SV2, is less abundant in these neurons. Without enough of this protein, the neurons are not able to send enough signal to muscles.

How do you think the results of this study might impact future approaches to the treatment of ALS?

This study provides evidence that even when a motor neuron doesn’t die, it can still be “broken” due to mutations that cause ALS. Importantly, these findings will guide future studies toward understanding both 1) how the motor neurons are dying, and 2) the health and function of the neurons that do not die.

Ben Zaepfel
Ph.D. Candidate | Rothstein Lab
Biochemistry, Cellular and Molecular Biology Ph.D. Program
The Johns Hopkins School of Medicine

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