Investigating molecular mechanisms behind neuronotypic GBA1 mutations in Lewy body dementias

Authors

• Casey Mahoney-Crane, University of Alabama at Birmingham

Advisor(s)

Laura Volpicelli-Daley

Committee Member(s)

Andrew Arrant
Ashley Harms
Elizabeth Sztul
Joesph Mazzulli
Karen Gamble

School

Joint Health Sciences (Interdisciplinary)

Document Type

Dissertation

Department (new version)

Neurobiology

Date of Award

9-9-2024

Abstract

Nonmotor deficits are present in nearly all Parkinson’s disease (PD) patients, with ~80% of these patients developing dementia. Importantly, expression of the severe GBA1 L444P heterozygous mutation increases the risk for Parkinson’s disease devel-opment by 5.43 times compared to mild mutation carriers. Currently, many PD treat-ments predominately focus motor symptoms, while treatments for nonmotor symptoms, such as visual-spatial difficulties and dementia, focus on symptom management and continue to remain elusive. Therefore, understanding the molecular mechanisms behind these nonmotor symptoms is essential for the development of effective therapeutics leading to slower disease progression. The work presented in this dissertation sought to determine the underlying mechanistic role of GBA1L444P expression in Lewy body dementias. This was accomplished by addressing two questions: 1) how does GBA1L444P expression contribute to the phenotypes in GBA1-associated Parkinson’s disease (Chap-ter 2)? And 2) what contributes to the cortical-hippocampal-dependent behavioral im-pairments due to GBA1L444P expression (Chapter 3)? In our GBA1L444P heterozygous murine model (GBA1+/L444P), GBA1+/L444P mice demonstrated impairments in contextual fear memory at 3-months of age and spatial working memory at 12-months of age. Ad-ditionally, GBA1L444P expression leads to an increase in excitatory synaptic markers and a decrease in inhibitory synaptic markers, solely in the entorhinal cortex. While treatment with venglustat, a glucosylceramide synthase inhibitor, did not rescue behav-ioral or pathologic phenotypes, expression of wildtype GCase into the entorhinal cortex rescued cortical GCase activity and inhibitory synaptic count in compared to controls. These findings suggest that GCase activity deficiency plays a vital role in synaptic abundance. Collectively, the work presented supports the need to investigate regional vulnerability as it pertains to GBA1-PD and cognitive decline.

ProQuest ID

https://proquest.com/docview/3101937378