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University of California, San Diego

La Jolla Center for Neurodegeneration Science,
Sanford-Burnham Medical Research Institute,
Salk Institute for Biological Sciences,
The Scripps Research Institute



Stuart A. Lipton, M.D., Ph.D.
slipton@sanfordburnham.org

Project Description:

The La Jolla Center for Neurodegenerative Science uses cell and animal models to study how the environment interacts with genes and gene products to lead to Parkinson’s disease. Understanding these gene-environment interactions could lead to new therapies and reveal measurable biological indicators, known as biomarkers, which would be useful for early detection. Potential biomarkers are then vetted on human brain tissue.

 

The center has discovered that proteins involved in Parkinson’s disease undergo chemical modifications in response to environmental contaminants (pesticides/herbicides/fungicides). These modifications mimic or enhance genetic mutations involved in inherited forms of Parkinson’s disease and cause problems that eventually lead to injury and death of neurons. Researchers from the center use high-throughput screening to identify drugs that might offset damage caused by these modifications and to identify biomarkers associated with Parkinson’s disease.


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Project Highlights

Sanford-Burnham’s Lipton, left, and Emory’s Dean Jones, Ph.D., took advantage of the poster session at an NIEHS meeting to continue their collaboration, which is an important component of the Centers for Neurodegeneration Science program
Sanford-Burnham’s Lipton, left, and Emory’s Dean Jones, Ph.D., took advantage of the poster session at an NIEHS meeting to continue their collaboration, which is an important component of the Centers for Neurodegeneration Science program.
(Photo courtesy of Steve McCaw)

Project 1: Regulation of parkin and PINK1 neddylation by Parkinson’s disease environmental neurotoxins 

Project leader: Zhuohua Zhang, Ph.D.

benzz@sanfordburnham.org

 

The chemical modification known as protein neddylation is important for regulating protein structure and function. The researchers involved in this project are studying this modification and have shown that the proteins parkin and PINK1, which are both associated with Parkinson’s disease, undergo neddylation.

 

Project 2: Interactions of PINK1 and p53 and their modulation by environmental toxins in drosophila Parkinson’s disease models 

Project leader: Rolf Bodmer, Ph.D.

rolf@sanfordburnham.org

 

The researchers involved in this project developed a fruit fly model of Parkinson’s disease to investigate the role of mutations in the protein PINK1. Interfering with the function of PINK1 in the nervous system is known to strongly affect muscle function. They also study oxidative post-translational modifications of PINK1 and other Parkinson’s-related proteins. The investigators also use their fly model to screen for chemical compounds that hold potential as therapies for Parkinson’s disease.  

 

Project 3: S-Nitrosylation affects protein misfolding and contributes to Parkinson’s disease induced by environmental toxins 

Project leaders: Stuart A. Lipton, M.D., Ph.D., and Eliezer Masliah, M.D.

slipton@sanfordburnham.org ; emasliah@ucsd.edu

 

This group has shown that pesticide/herbicide/fungicide exposure can lead to oxidative modifications of proteins involved in Parkinson’s disease. These chemical modifications appear to contribute to the development of Parkinson’s disease and can mimic or enhance inherited mutations in genes involved in Parkinson’s disease. The investigators screen chemical libraries to find small molecules that can prevent these redox modifications that involve S-nitrosylation or sulfonation (the addition of NO or reactive oxygen species, respectively, to a critical cysteine thiol group on a protein). They are also developing biomarkers of Parkinson’s disease based on these chemical modifications.  

 

Project 4: A developmental perspective to nitrosative/oxidative susceptibility 

Project leaders: Alexey Terskikh, Ph.D., and Evan Snyder, M.D., Ph.D.

terskikh@sanfordburnham.org ; esnyder@sanfordburnham.org

 

In this project, researchers use stem cells to model the development of human dopamine-secreting neurons. This model lets them study the effect of pesticides, fungicides, and herbicides on different developmental stages of dopaminergic neurons. Findings from these studies could lead to new drugs that protect neurons from the effects of environmental exposures that contribute to neuronal damage in Parkinson’s disease.
 

http://tools.niehs.nih.gov/portfolio/index.cfm/portfolio/grantPubDetail/grant_number/P01ES016738

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Selected Publications:

  • Cho D-H, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-Nitrosylation of Drp1 mediates β-amyloid-related mitochondrial fission and neuronal injury. Science 2009;324:102-105.
  • Choo YS, Vogler G, Wang D, Kalvakuri S, Iliuk A, Tao WA, Bodmer R, Zhang Z. Regulation of parkin and PINK1 by neddylation. Hum Mol Genet 2012; Mar 8. [Epub ahead of print]. PMID: 22388932
  • Desplats P, Spencer B, Coffee E, Patel P, Michael S, Patrick C, Adame A, Rockenstein E, Masliah E. alpha-synuclein Sequesters DNMT1 from the Nucleus: A novel mechanism for epigenetic alterations in Lewy body Disease. J Biol Chem 2011;286(11):9031-7. Epub 2011 Feb 4. PMCID: PMC3059002
  • Gu Z, Nakamura, T, Lipton SA. Redox reactions induced by nitrosative stress mediate protein misfolding and mitochondrial dysfunction in neurodegenerative diseases. Mol Neurobiol 2010;41:55-72.
  • Lakshmanane Premkumar, Małgorzata K. Dobaczewska, Stefan J. Riedl. Identification of an artificial peptide motif that binds and stabilizes reduced human DJ-1. Journal of Structural Biology 2011;176 414–418.
  • Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA*, Ding S*. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions.  Cell Stem Cell 2011;9:113-118. (*co-corresponding authors).
  • Lee, J.H., Budanov, A.V., Park, E.J., Birse, R., Kim, T.E., Perkins, G.A., Ocorr, K., Ellisman, M.H., Bodmer, R., Bier, E. and Karin, M. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 2010;327, 1223-1228. 2919257.
  • Meng F, Yao D, Shi Y, Kabakoff J, Wu W, Reicher J, Ma Y, Moosmann B, Masliah E, Lipton SA, Gu Z. Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation. Mol Neurodegen 2011;6:34-49.
  • Nakamura T, and Lipton SA. Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death:  potential implications for Alzheimer’s and Parkinson’s diseases. Apoptosis 2010;15, 1354-63.
  • Nakamura T, Wang L, Wong CCL, Scott FL, Eckelman BP, Han X, Tzitzilonis C, Meng F, Gu Z, Holland EA, Clemente AT, Okamoto S-i, Salvesen GS, Riek R, Yates JR 3rd, and Lipton SA. Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death. Mol Cell 2010;39, 184-95.
  • Numajiri N, Takasawa K, Nishiya T, Hayakawa W, Asada M, Matsuda H, Azumi K, Tanaka H, Hyakkoku K, Kamata H, Nakamura T, Hara H, Minami M, Lipton SA, Uehara T. On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN). Proc Natl Acad Sci USA 2011;108:10349-10354.
  • Qu J, Nakamura T, Cao G, Holland EA, McKercher SR, Lipton SA. S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide. Proc Natl Acad Sci USA 2011;108:14330-14335.
  • Satoh T, Razie T, Seki M, Tabuchi T, Kitagawa T, Yanagitai M, Senzaki M, Kosegawa C, Taira H, McKercher SR, Hoffman JK, Roth GP, Lipton SA. Dual neuroprotective pathways of a pro-electrophilic compound via HSF-1-activated heat-shock proteins and Nrf2-activated phase 2 antioxidant response enzymes. J Neurochem 2011;119:569-578.
  • Shi Y, Kabakoff J, Wu W, Reicher J, Ma Y, Moosmann B, Masliah E, Lipton SA, Gu Z. Oxidation of cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation. Mol Neurodegen 2011;6:34. [PMID: 21595948]
  • Ubhi K, Rockenstein E, Mante M, Inglis C, Adame A, Patrick C, Masliah E. Alpha-synuclein deficient mice are resistant to neurotoxin-induced multiple system atrophy injury. Neuroreport. 2010 Apr 21;21(6):457-62. PMCID: PMC3049936
  • Venderova, K., Kabbach, G., Abdel-Messih, E., Zhang, Y., Parks, R.J., Imai, Y., Gehrke, S., Ngsee, J., Lavoie, M.J., Slack, R.S., Rao, Y., Zhang, Z., Lu, B., Haque, M.E., and Park, D.S. Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease. Hum Mol Genet 2009;18:4390-4404.
  • Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, Tzitzilonis C, Soragni A, Jessberger S, Mira H, Consiglio A, Pham E, Masliah E, Gage FH, Riek R. In vivo demonstration that {alpha}-synuclein oligomers are toxic. Proc Natl Acad Sci USA 2011;108:4194-4299. Epub 2011 Feb 15. PMCID: PMC3053976
  • Xiong, H., Wang, D.L., Chen, L., Choo, Y.S., Ma, H., Tang, C.Y., Xia, X., Jiang, W., Ronai, Z., Zhuang, X., Zhang, Z. Parkin, PINK1, and DJ-1 form a novel E3 ligase complex to promote unfolded protein degradation. J Clin Invest 2009;119:650-660.  PMCID: PMC2648688.


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