Research
The lab studies basic mechanisms that are involved in the production and degeneration of neurons in the brain:
1. How does the developing brain regulate the number of neurons that it produces?
2. What cellular mechanisms lead to neuronal degeneration in Parkinson's Disease?
Question One: How does the developing brain regulate the number of neurons that it produces?
The brain begins as a thin layer of neural stem cells that divide to produce neurons for the growing and developing tissue. How long the dividing cells remain mitotically active is crucial for determining how many neurons will be produced, and ultimately, how large the brain might grow. If they stop dividing too soon, too few neurons may be produced. On the other hand, if they divide for too long – even just one extra cell cycle – too many neurons may result. How do stem cells “know” when to stop dividing? Complex regulatory mechanisms likely ensure that the cells undergo the correct number of cell divisions and that the brain forms properly. Our lab is interested in the mechanisms that underlie the process of neuronal proliferation in the developing brain. In particular, we use multicolor fluorescence to color-code dividing cells and their progeny. Using fluorescence imaging tools we can study interactions both within and among dividing clones of cells. We can also follow the fate of individual newborn neurons
Question Two: What cellular mechanisms lead to neuronal degeneration in Parkinson's Disease?
While our lab studies the mechanisms that regulate neuron development, we are also interested in mechanisms that lead to neuron dysfunction. One such mechanism involves the abnormal aggregation of a protein called alpha-synuclein during Parkinson’s Disease. In collaboration with Dr. Vivek Unni’s lab at Oregon Health & Science University (OHSU), we have established a zebrafish model for studying alpha-synuclein function in the living brain. Because zebrafish are transparent during development, we are able to visualize a fluorescence-tagged form of alpha-synuclein in vivo using confocal microscopy.
Publications
Undergraduate co-authors are listed in bold (some include work done during year following their graduation)
Dent SE, King DP, Osterberg VR, Adams EK, Mackiewicz MR, Weissman TA, Unni VK. Phosphorylation of the aggregate-forming protein alpha-synuclein on serine-129 inhibits its DNA-bending properties. J Biol Chem. 2022 Feb;298(2):101552. doi: 10.1016/j.jbc.2021.101552. Epub 2021 Dec 30. PMID:34973339; PMCID: PMC8800120.
Weston LJ, Cook ZT, Stackhouse TL, Sal MK, Schultz BI, Tobias ZJC, Osterberg VR, Brockway NL, Pizano S, Glover G, Weissman TA, Unni VK. In vivo aggregation of presynaptic alpha-synuclein is not influenced by its phosphorylation at serine-129. Neurobiol Dis. 2021 May;152:105291. doi: 10.1016/j.nbd.2021.105291. Epub 2021 Feb 5. PMID: 33556542; PMCID: PMC10405908.
Weston LJ, Stackhouse TL, Spinelli KJ, Boutros SW, Rose EP, Osterberg VR, Luk KC, Raber J, Weissman TA, Unni VK. Genetic deletion of Polo-like kinase 2 reduces alpha-synuclein serine-129 phosphorylation in presynaptic terminals but not Lewy bodies. J Biol Chem. 2021 Jan-Jun;296:100273. doi: 10.1016/j.jbc.2021.100273. Epub 2021 Jan 9. PMID: 33428941; PMCID: PMC7948797.
Cook ZT, Brockway NL, Weissman TA. Visualizing the Developing Brain in Living Zebrafish using Brainbow and Time-lapse Confocal Imaging. J Vis Exp. 2020 Mar 23;(157). doi: 10.3791/60593. PMID: 32250362.
Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, Weston LJ, Owen N, Weissman TA, Luna E, Raber J, Luk KC, McCullough AK, Woltjer RL, Unni VK. Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Sci Rep. 2019 Jul 29;9(1):10919. doi: 10.1038/s41598-019-47227-z. PMID: 31358782; PMCID: PMC6662836.
Brockway NL, Cook ZT, O'Gallagher MJ, Tobias ZJC, Gedi M, Carey KM, Unni VK, Pan YA, Metz MR, Weissman TA. Multicolor lineage tracing using in vivo time-lapse imaging reveals coordinated death of clonally related cells in the developing vertebrate brain. Dev Biol. 2019 Sep 15;453(2):130-140. doi:10.1016/j.ydbio.2019.05.006. Epub 2019 May 16. PMID: 31102591; PMCID:PMC10426338.
Cook ZT, Brockway NL, Tobias ZJC, Pajarla J, Boardman IS, Ippolito H, Nkombo Nkoula S, Weissman TA. Combining near-infrared fluorescence with Brainbow to visualize expression of specific genes within a multicolor context. Mol Biol Cell. 2019 Feb 15;30(4):491-505. doi: 10.1091/mbc.E18-06-0340. Epub 2018 Dec 26. PMID: 30586321; PMCID: PMC6594444.
Marra MH, Tobias ZJ, Cohen HR, Glover G, Weissman TA. In Vivo Time-Lapse Imaging in the Zebrafish Lateral Line: A Flexible, Open-Ended Research Project for an Undergraduate Neurobiology Laboratory Course. J Undergrad Neurosci Educ. 2015 Jul 7;13(3):A215-24. PMID: 26240532; PMCID: PMC4521740.
Weissman TA, Pan YA. Brainbow: new resources and emerging biological applications for multicolor genetic labeling and analysis. Genetics. 2015 Feb;199(2):293-306. doi: 10.1534/genetics.114.172510. PMID: 25657347; PMCID: PMC4317644.
Hamling KR, Tobias ZJ, Weissman TA. Mapping the development of cerebellar Purkinje cells in zebrafish. Dev Neurobiol. 2015 Nov;75(11):1174-88. doi:10.1002/dneu.22275. Epub 2015 Feb 18. PMID: 25655100.
Funding
The Weissman Lab is generously supported by the following:
National Institutes of Health (1R15NS128688-01A1)
With previous funding from:
National Science Foundation
M. J. Murdock Charitable Trust
Collins Medical Trust
Fischer Family Foundation
AJW Foundation
John S. Rogers Science Program at Lewis & Clark College