Traumatic Brain Injury (TBI) can result in the disturbance of cognitive, behavioral, emotional, and physical functioning. Residual cognitive disturbance remains the most significant concern of persons with all severities of TBI. Normal brain cognitive function depends on synaptic connectivity via neurotransmitter release. We have previously shown that experimental TBI can produce persistent deficits in evoked neurotransmitter release, but the mechanisms are unknown. Neurotransmitter release at the synapse requires fusion of synaptic vesicles with the presynaptic plasma membrane. We have data that a crucial step in this process involving the assembly of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is impaired after TBI. This concept is supported by novel ultra-structural preliminary data that demonstrate a reduction of vesicles near the synaptic active zone after TBI. We have also found that proteins important to the assembly of SNARE complexes are decreased after TBI. Cysteine string protein alpha (CSP?), which promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity, is reduced after TBI. Alpha (?)-synuclein is a protein localized mainly in synapses wher it is thought to function in the regulation of synaptic transmission via interaction with specific pools of synaptic vesicles, thereby modulating synaptic functions in the normal brain. There is evidence that a normal role of ?-synuclein is to assist in SNARE complex formation through its interaction with VAMP2. We have preliminary data that native ?-synuclein is decreased from 6hrs to 4 weeks after experimental TBI, suggesting impaired normal function of ?-synuclein. Relevant to this project are recent reports demonstrating that 1) a genetic knock-out of ?-synuclein can reduce the number of vesicles at the presynaptic terminal () and 2) that ?-synuclein can rescue neurons that genetically lack CSPa (). Since both distal synaptic vesicles and CSP? are diminished after TBI, we hypothesize that therapies that restore normal wild-type ?-synuclein levels after TBI will prevent SNARE complex assembly deficits and improve neurotransmitter release and cognitive function after TBI.
The first Aim will examine the effects of TBI on wild-type and cytotoxic forms of ?-synuclein.
The second Aim will determine the effects of over-expression of ?-synuclein on markers of SNARE protein complex assembly, neurotransmitter release, and cognition. The last Aim will determine if restoring (post-TBI) wild-type ?-synuclein levels can attenuate SNARE protein complexes, increase distal pools of synaptic vesicles, prevent neurotransmitter release deficits, and improve behavioral function.
This Aim i s supported by preliminary data demonstrating that docosahexaenoic acid (DHA), which has been shown to increase ?-synuclein, can attenuate the post-injury loss of wild-type ?-synuclein. While the neurodegenerative properties of ?-synuclein have been a major research area, the concept of restoring ?-synuclein homeostasis represents a novel target of therapeutic intervention after TBI.

Public Health Relevance

Alpha synuclein is a presynaptic protein that normally functions to promote neurotransmitter release. Traumatic brain injury reduces normal alpha-synuclein levels in brain regions associated with memory function. This project seeks to determine if restoring alpha-synuclein to physiologic levels will improve neurotransmitter release and cognitive function after traumatic brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091062-05
Application #
9645678
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213