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Astrocytic Mitochondria: Tools to Study and Implications in Parkinson's Disease
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder primarily characterized by progressive motor dysfunction and currently has no cure. Research has elucidated coalescing molecular dysfunctions including neuroinflammation, alpha-synuclein proteostasis, mitochondrial dysfunction, and oxidative stress underlying the main pathological hallmarks of PD, which are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and aggregation of alpha-synuclein. Historically, study of these perturbations has been centered on neurons, but increasing evidence indicates that molecular dysfunctions in astrocytes play a significant role in PD progression.
Astrocytes are the most abundant cell type in the central nervous system representing over 30% of all cell types. While early descriptions of astrocytes labeled them as passive structural supports for neurons, ongoing research has shed light on critical functions of astrocytes in physiological and pathological states. One way astrocytes govern critical brain functions is via a plethora of Ca^2+ signals, with a significant proportion of these signals associated with mitochondria. Given that several lines of evidence converge on mitochondrial dysfunction as a common pathway in neurodegeneration, there exists a high likelihood that mitochondrial dysfunction in astrocytes affects PD progression and may represent a disease modifying target.
Until recent years molecular tools to study astrocytes at a subcellular level did not exist. In order to address this knowledge gap, I developed and characterized two adeno associated viruses (AAVs) targeting the matrix of astrocytic mitochondria for study of Ca^2+ signaling and morphology. I first characterized Ca^2+ influx sources and kinetics,
Following extensive literature review, I then developed and characterized a mouse model utilizing SNc injection of AAV alpha-synuclein to recapitulate early PD pathology. I discovered sexual dimorphisms in neurodegeneration along with female specific changes in striatal astrocytic mitochondrial Ca^2+ kinetics and morphology after 5 months of alpha-synuclein overexpression. These results further substantiate the importance of astrocytic mitochondria in health and disease and identify a novel finding on the sex specificity of this powerhouse organelle in PD pathology.
finding that astrocytic mitochondria possess unique properties with regard to morphology, Ca^2+ influx mechanisms, and responses to neurotransmitter receptor agonists within individual astrocytes and across two distinct brain regions.
Citation
Huntington, Taylor Elise (2022). Astrocytic Mitochondria: Tools to Study and Implications in Parkinson's Disease. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /198567.