Areas of investigation/research focus

As an independent investigator my main question is why neurodegenerative diseases (NDs) target specific brain regions, at least initially, a feature known as selective vulnerability {Jackson, 2014 #2465}. For example, brain regions important for motor control are severely damaged in Huntington’s disease (HD), while brain regions important for memory are severely damaged in Alzheimer’s disease. Since these and many other neurodegenerative diseases are thought to be caused by misfolding of specific proteins, a reasonable explanation is that the regions affected the most have the highest expression levels of the toxic proteins. However this is not the case, and something else must be determining selective vulnerability.

Although we typically speak of selective vulnerability in the context of specific brain regions being affected, in reality it is specific cell types of specific regions that are affected. We hypothesize that different diseases will trigger cell type-specific changes in gene regulation. This led me to develop a research program to study how specific cell-types alter their gene regulation strategies in response to different stressors. During the last six years we have focused on three main projects that are highly intertwined: 1) the propensity of misfolded proteins linked to NDs to spread across the brain, 2) the interplay of age related sleep loss and NDs, and 3) cell type-specific gene-expression responses to protein misfolding stressors.

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We have two basic questions regarding selective vulnerability: 1) Does a given brain cell respond differently to different protein misfolding stressors and 2) Do different cell types respond to the same stressor differently? We hypothesize that the protein quality control machinery differs between different cell types due to different compilations of machinery components and clients and these differences strongly influence selective vulnerability (Jackson, 2014). Existing methods in the lab were not sufficient to study the phenotypes of specific cell types in the brain. Therefore, we have integrated a technique that enables the isolation of mRNAs from the cells of interest. This is accomplished by expressing in specific cell types a modified ribosome protein (called RiboTag) that carries an antibody epitope and incorporates into translating ribosomes (Sanz et al., 2009). The RiboTag bearing ribosomes and the mRNAs attached to them are affinity purified from crude brain homogenates and the attached mRNAs are then purified and analyzed by QPCR and next generation sequencing. The enrichment and depletion of known cell type markers demonstrate the specificity of the mRNA purifications. This powerful tool accomplishes two special objectives at once: 1) it captures mRNA from specific cell types, and 2) it specifically captures mRNAs that are being translated, which correlates with the proteome much better than total mRNAs (Battle et al., 2015). Furthermore, since the tissues are first frozen, mRNA is well preserved, which can be difficult to achieve with methods that physically separate cells or cell bodies.

Key Publications

Lech Kaczmarczyk, Ylva Mende, Branko Zevnik, Walker S. Jackson. Manipulating the prion protein gene sequence and expression levels with CRISPR/Cas9. PLoS ONE. 2016 Mar 31; 11 doi: 10.1371/journal.pone.0154604
Walker S. Jackson. Selective vulnerability to neurodegenerative disease: The curious case of Prion Protein. DMM Disease Models and Mechanisms. 2013 Dec 31; 7:21-29. doi: 10.1242/dmm.012146
Jackson WS, Krost C, Borkowski AW, Kaczmarczyk L. Translation of the prion protein mRNA is robust in astrocytes but does not amplify during reactive astrocytosis in the mouse brain. PLoS One. 2014 Apr 21; 9:e95958. doi: 10.1371/journal.pone.0095958
Jackson WS, Borkowski AW, Watson NE, King OD, Faas H, Jasanoff A, Lindquist S. Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases. Proc Natl Acad Sci U S A. 2013 Sep 03; 110:14759-64. doi: 10.1073/pnas.1312006110
Jackson WS, Borkowski AW, Faas H, Steele AD, King OD, Watson N, Jasanoff A, Lindquist S. Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice. Neuron. 2009 Aug 27; 63:438-50. doi: 10.1016/j.neuron.2009.07.026


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