Have you or someone you know played the game “Telephone?” In this game, a group of people are in a circle and share a message starting with Person A all the way until it reaches the last person. You can think of our synapses functioning in the same way. But what happens if Person A tries to share the message, but there is no Person B to carry it forward? This generates a physical gap hindering the message from reaching the final person. This principle mimics cellular dysfunction in neurodegenerative disease when synaptic degeneration occurs.

Throughout my time as a graduate student in the Lab of Dr. Laura Volpicelli-Daley, I investigated the underlying mechanism behind synaptic degeneration in a Parkinson’s disease (PD) mouse model. The gene GBA1 encodes for the lysosomal enzyme, Glucocerebrosidase (GCase) which enzymatically cleaves glycolipids, including glucosylceramide to glucose and ceramide. Interestingly, PD patients who carry one copy of a GBA1 mutation (a heterozygous mutation) demonstrate over a 5-fold increased risk of developing dementia compared to those without carrying a GBA1 mutation. Indeed, carriers of a severe mutation, such as a L444P mutation, further demonstrate enhanced risk of developing dementia compared to those carrying a mild mutation such as the N370S.

But why and how would a dysfunctional lysosomal enzyme contribute to nonmotor deficits including learning and memory? This is the underlying question addressed in my thesis work. To begin addressing this work, I performed a series of behavioral tests and showed short-term spatial working memory deficits. Underlying these behavioral phenotypes, the GBA1L444P mutation may play a role in synapse density as demonstrated by an increase in excitatory synapses and a decrease in inhibitory synapses solely in the entorhinal cortex, compared to wildtype controls. Thus, communication across brain regions important for memory may be inhibited. Importantly, increasing GCase activity in the entorhinal cortex rescues inhibitory synaptic degeneration. Therefore, these data warrant further investigation to determine why GCase activity would influence cell-type specific changes.

The lysosome, which can be thought of like a trash can, is necessary to help clean up clutter within our cells. When lysosomal dysfunction occurs, the garbage builds up leading to harmful downstream effects including motor and nonmotor deficits through an unknown mechanism. By focusing on increasing overall lysosome function as a target for therapy, we hope to slow disease progression ultimately improving the quality of life for those affected by Parkinson’s disease.

Casey Mahoney-Crane, PhD she is doing a postdoctoral fellowship with Dr. Mark Cookson at the NIH: National Institute of Aging, Laboratory of Neurogenetics. She was a poster presenter at the WPC 2023 in Barcelona.

𝕏: @df_lazaro

Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®