Abstract

Elucidating the physiological function of alpha-synuclein is important because mutations in this protein are implicated as a causative factor in familial Parkinson disease (PD) and because alpha-synuclein is associated with a number of other neurodegenerative diseases. Preliminary data contained herein indicates that alpha-synuclein dramatically affects steady-state lipid mass in brain and in isolated synaptosomes, suggesting that alpha-synuclein has a significant impact on brain phospholipid metabolism. Collectively, these changes, along with others, could alter the basal biophysical state of the membrane as well as decrease intracellular second messenger generation via a reduction in lipid-mediated signaling. Thus, it is critical to address the mechanism(s) by which alpha-synuclein affects brain lipid metabolism to gain a greater understanding regarding the potential physiological role for alpha-synuclein in the brain. The following specific aims are designed to address the impact that alpha-synuclein has on brain phospholipid metabolism using a combination of whole animal, cell culture, and in vitro approaches.
Aim 1. Determine the effect alpha-synuclein on brain phospholipid metabolism in vivo using steady-state radiotracer kinetics to assess the kinetics phospholipid biosynthesis and downstream processing in alpha-synuclein gene-abated and control mice.
Aim 2. Determine the effect of alpha-synuclein on cellular phospholipid metabolism ex vivo using stable isotopes and radiotracers to assess the kinetics of phospholipid biosynthesis and downstream processing in neurons and glia isolated from alpha-synuclein gene-abated and control mice.
Aim 3. Compare the effects of mutant and wild-type alpha-synuclein on phospholipid metabolism in stably transfected HEK-293 cells using stable isotopes and radiotracers to assess the kinetics of phospholipid biosynthesis and downstream processing.
Aim 4. Determine the ability of wild-type and mutant alpha-synuclein to directly alter phospholipid biosynthesis in vitro using a combination of approaches.
These aims are designed to address the following hypothesis: alpha-Synuclein stimulate phospholipid synthesis through a direct stimulation of phosphatidic acid biosynthesis, thereby increasing the phosphatidic acid pool available for use in downstream synthesis of specific phospholipids.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
1P20RR017699-01
Application #
6688856
Study Section
Special Emphasis Panel (ZRR1)
Project Start
2002-09-15
Project End
2007-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost

  Institution

Name
University of North Dakota
Department
Type
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202

  Publications

Kulas, Joshua A; Puig, Kendra L; Combs, Colin K (2017) Amyloid precursor protein in pancreatic islets. J Endocrinol 235:49-67
Krout, Danielle; Pramod, Akula Bala; Dahal, Rejwi Acharya et al. (2017) Inhibitor mechanisms in the S1 binding site of the dopamine transporter defined by multi-site molecular tethering of photoactive cocaine analogs. Biochem Pharmacol 142:204-215
Sukumaran, Pramod; Schaar, Anne; Sun, Yuyang et al. (2016) Functional role of TRP channels in modulating ER stress and Autophagy. Cell Calcium 60:123-32
Puig, Kendra L; Kulas, Joshua A; Franklin, Whitney et al. (2016) The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice. Neurobiol Aging 40:22-40
Liu, Qing Yan; Koukiekolo, Roger; Zhang, Dong Ling et al. (2016) Molecular events linking cholesterol to Alzheimer's disease and inclusion body myositis in a rabbit model. Am J Neurodegener Dis 5:74-84
Moritz, Amy E; Rastedt, Danielle E; Stanislowski, Daniel J et al. (2015) Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics. J Biol Chem 290:29095-105
Zhou, Xikun; Ye, Yan; Sun, Yuyang et al. (2015) Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase C? Signaling. Mol Cell Biol 35:2729-39
Zhang, Shuang; Yu, Min; Guo, Qiang et al. (2015) Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway. Sci Rep 5:15859
Puig, Kendra L; Lutz, Brianna M; Urquhart, Siri A et al. (2015) Overexpression of mutant amyloid-? protein precursor and presenilin 1 modulates enteric nervous system. J Alzheimers Dis 44:1263-78
Rojanathammanee, Lalida; Floden, Angela M; Manocha, Gunjan D et al. (2015) Attenuation of microglial activation in a mouse model of Alzheimer's disease via NFAT inhibition. J Neuroinflammation 12:42

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