Photo of the dynamic structure “Soma” at Pier 14. Soma was constructed by Robin Bishop (Swanson Lab 2014 - 2018) and the Flaming Lotus Girls. https://www.flaminglotusgirls-serenity.com/soma. Photo by Lorah Gross.
We aim to identify therapies for stroke, Parkinson’s disease, and
related disorders. Our focus is on bionenergetics and neuronal
responses to oxidative stress.
CURRENT PROJECTS
Parkinson's Disease
A fascinating aspect of Parkinson’s disease is that identical phenotypes result from both purely genetic and purely environmental influences. We propose that genetic and environmental factors act by a final common pathway involving a “gain of function” property of α-synuclein aggregates. Specifically, we are exploring the possibility that metal binding to epitopes exposed on these aggregates promotes the formation of reactive oxygen species, and that increased formation of reactive oxygen species in turn promotes α-synuclein aggregate formation.
Our work indicates that neuronal glutathione metabolism is a crucial factor limiting aggregate formation and oxidative stress, and we are exploring clinically feasible ways of supporting neuronal glutathione production as clinical therapeutic approach.
In coordination with the labs of Sam Goldman (UCSF) and Stephen Finkbeiner (UCSF & Gladstone Institutes), we are also using CRISPR-edited human iPSC - derived dopaminergic neurons to evaluate specific gene variants which may render individuals more likely to develop Parkinson’s disease when exposed to agricultural and other toxicants.
Stroke
Decades of stroke research have focused on factors leading to death of neuronal cell bodies, but have generally ignored factors which lead to demise of neuronal dendrites. Dendrites are often irreversibly damaged by brain ischemia even when the parent neuron survives, resulting in a loss of network connectivity, which may or may not recover. We have identified the formation of cofilin-actin rods as a factor causing demise of distal dendrites. Cofilin-actin rod formation is induced by focal oxidative stress, and can be suppressed by both genetic and pharmacological interventions. Our current work aims to elucidate the biochemical mechanisms driving rod formation and to determine if blocking rod formation can improve outcomes after stroke. Behavioral assessments for these studies are being done in collaboration with the Ganguly lab (UCSF), which has developed a skilled reaching assay for rodent stroke impairment that is highly sensitive well-characterized with respect to parallel electrophysiological network changes.
In a separate project, we are evaluating the effects of hyperglycemia after stroke on both the inflammatory response and on cell and dendrite survival. This project is of high clinical relevance because hyperglycemia frequently complicates stroke and the clinical indications for glucose management are unclear. Our findings indicate that hyperglycemia promotes reactive oxygen formation in peri-infarct tissue, and that outcomes can be improved either by glucose normalization or by blocking NADPH oxidase function.
Superoxide channels and glycogen
Relevant to both of the above projects, we are interested in identifying the route by which reactive oxygen species, specifically superoxide, gains entrance into neurons. Our data indicates that this is done through a specific anion channel, and that the spatial distribution and activity of this channel are regulated.
The Swanson lab has had a very long interest in the role of glycogen in brain. Brain glycogen is localized primarily to astrocytes, and we showed long ago that astrocyte glycogen metabolism is tightly coupled to nearby neuronal activity. Astrocyte glycogen is widely considered to function as a local “glucose reserve”, but we argue instead that it has an entirely different role. We propose that serves a thermodynamic function, to maintain the energy yield from ATP utilization particularly in spatially constrained astrocyte processes. We aim to confirm this proposal using molecular probes with subcellular resolution in brain slice preparations.
Parkinson's Disease
A fascinating aspect of Parkinson’s disease is that identical phenotypes result from both purely genetic and purely environmental influences. We propose that genetic and environmental factors act by a final common pathway involving a “gain of function” property of α-synuclein aggregates. Specifically, we are exploring the possibility that metal binding to epitopes exposed on these aggregates promotes the formation of reactive oxygen species, and that increased formation of reactive oxygen species in turn promotes α-synuclein aggregate formation.
Our work indicates that neuronal glutathione metabolism is a crucial factor limiting aggregate formation and oxidative stress, and we are exploring clinically feasible ways of supporting neuronal glutathione production as clinical therapeutic approach.
In coordination with the labs of Sam Goldman (UCSF) and Stephen Finkbeiner (UCSF & Gladstone Institutes), we are also using CRISPR-edited human iPSC - derived dopaminergic neurons to evaluate specific gene variants which may render individuals more likely to develop Parkinson’s disease when exposed to agricultural and other toxicants.
Stroke
Decades of stroke research have focused on factors leading to death of neuronal cell bodies, but have generally ignored factors which lead to demise of neuronal dendrites. Dendrites are often irreversibly damaged by brain ischemia even when the parent neuron survives, resulting in a loss of network connectivity, which may or may not recover. We have identified the formation of cofilin-actin rods as a factor causing demise of distal dendrites. Cofilin-actin rod formation is induced by focal oxidative stress, and can be suppressed by both genetic and pharmacological interventions. Our current work aims to elucidate the biochemical mechanisms driving rod formation and to determine if blocking rod formation can improve outcomes after stroke. Behavioral assessments for these studies are being done in collaboration with the Ganguly lab (UCSF), which has developed a skilled reaching assay for rodent stroke impairment that is highly sensitive well-characterized with respect to parallel electrophysiological network changes.
In a separate project, we are evaluating the effects of hyperglycemia after stroke on both the inflammatory response and on cell and dendrite survival. This project is of high clinical relevance because hyperglycemia frequently complicates stroke and the clinical indications for glucose management are unclear. Our findings indicate that hyperglycemia promotes reactive oxygen formation in peri-infarct tissue, and that outcomes can be improved either by glucose normalization or by blocking NADPH oxidase function.
Superoxide channels and glycogen
Relevant to both of the above projects, we are interested in identifying the route by which reactive oxygen species, specifically superoxide, gains entrance into neurons. Our data indicates that this is done through a specific anion channel, and that the spatial distribution and activity of this channel are regulated.
The Swanson lab has had a very long interest in the role of glycogen in brain. Brain glycogen is localized primarily to astrocytes, and we showed long ago that astrocyte glycogen metabolism is tightly coupled to nearby neuronal activity. Astrocyte glycogen is widely considered to function as a local “glucose reserve”, but we argue instead that it has an entirely different role. We propose that serves a thermodynamic function, to maintain the energy yield from ATP utilization particularly in spatially constrained astrocyte processes. We aim to confirm this proposal using molecular probes with subcellular resolution in brain slice preparations.
Raymond A. Swanson, M.D.
Professor , Dept. of Neurology, UCSF
Neurology Service, San Francisco Veterans Affairs Medical Center
Faculty, Neuroscience Graduate Program and Biomedical Sciences Graduate Program
Rm 482, 1700 Owens St., San Francisco, CA 94158
Raymond.swanson@ucsf.edu
(415) 575-0403
Professor , Dept. of Neurology, UCSF
Neurology Service, San Francisco Veterans Affairs Medical Center
Faculty, Neuroscience Graduate Program and Biomedical Sciences Graduate Program
Rm 482, 1700 Owens St., San Francisco, CA 94158
Raymond.swanson@ucsf.edu
(415) 575-0403
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