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Nassrallah, Wissam

University of British Columbia

Huntington disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons in the striatum and cortex degenerate, leading to motor and cognitive disorders. Dysregulation of synaptic function and calcium handling is common in many neurodegenerative diseases. N-methyl-D-aspartate (NMDA) receptor function is enhanced at extrasynaptic sites, altering the balance of calcium-dependent neuronal survival vs. death signalling pathways. Another important level of calcium regulation is at the endoplasmic reticulum (ER), and this regulation is abnormal in HD. The ER is also suggested to be involved in nuclear calcium signalling, and I hypothesise that this signalling pathway is altered in HD. Sigma-1 receptors (S1Rs) – proteins located on the ER – play an important role in calcium regulation and thus gene transcription. Interestingly, activating S1Rs has been shown to normalise this ER calcium handling and restore synaptic function in HD mouse models. Furthermore, recent work has shown that overexpression of Activin A, a secreted protein whose transcription is nuclear-calcium-dependent, reduces toxic extrasynaptic NMDA receptor signalling in the hippocampus. The goal of this project is to determine the link between S1Rs, calcium handling, Activin A, and synaptic function to better understand the pathophysiological mechanisms of HD and to find new potential treatments. Neuronal cultures, imaging techniques, behavioural assessment, and electrophysiology were used to investigate these processes in a mouse model of HD. Our data shows contributions of different calcium channels to nuclear calcium signalling. Calcium imaging also suggests impairments in nuclear calcium signalling in HD striatal medium-sized spiny neurons in co-culture with cortical neurons, which was not corrected by treatment with S1R agonists. Furthermore, our data show that Activin A is decreased in HD culture media, and its overexpression normalises extrasynaptic NMDA receptor expression. Moreover, early injection of an Activin A AAV virus into the striatum led to a significant improvement in a motor coordination task at an age when HD mice are known to show impairment. This project has elucidated therapeutic benefits of Activin A in the treatment of HD; more research is needed to understand Activin A’s mechanism of action and further explore its potential benefits in other neurodegenerative diseases.

Text

2022-06-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81803

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/