Selective vulnerability to neurodegeneration

Research page Walker Jackson

Neurodegenerative diseases cause stereotypical signs based on the specific brain region that is targeted. We try to understand how unaffected regions resist disease with the hope that these secrets can be transferred to vulnerable brain regions.

Our lab addresses the question of why neurodegenerative diseases target specific brain regions, at least initially, a feature known as selective vulnerability. For example, brain regions important for motor control are severely damaged in Huntington’s disease, while brain regions important for memory are severely damaged in Alzheimer’s disease.

Genetic neurodegenerative diseases are especially enigmatic because all cells carry the disease inducing mutation and yet most resist the disease. Moreover, these mutations are expressed for decades before disease sets in. How does the brain resist the toxic protein for so long and why does it eventually fail?

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 effectiveness of 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. 

To study the phenotypes of specific cell types in the brain prior to disease onset, we have employed 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 a molecular handle which we use to capture translating ribosomes and determine which proteins the cells are attempting to make. 

Our work with RiboTag revealed that cells that are thought to resist disease show dramatic changes early, while cells that are severely affected late in disease show no response early. These surprising results inspired us to create a new technique that enables us to study multiple layers of gene regulation, from chromatin modulation to translation, all from specific cell types of complex tissues.  

 

Walker Jackson fov

Research group

News

Open positions

We are happy to receive applications from people interested in our work, who would like to perform an internship or a master thesis project in the lab.

We especially encourage students interested in pursuing a bioinformatic project involving R programming and/or building online shiny applications for visualizing scientific data. Minimum basic knowledge of R is required.

Please e-mail Lech Kaczmarczyk or Walker Jackson to discuss the possibilities.

Publications

Publications from DiVA

2024

Daniel J. Walsh, Judy R. Rees, Surabhi Mehra, Matthew E. C. Bourkas, Lech Kaczmarczyk, Erica Stuart, Walker Jackson, Joel C. Watts, Surachai Supattapone (2024) Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease PLoS Pathogens, Vol. 20, Article e1012087 Continue to DOI
Walker Jackson, Susanne Bauer, Lech Kaczmarczyk, Srivathsa Magadi (2024) Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies Biology, Vol. 13, Article 67 Continue to DOI

2023

Sonia M. Vallabh, Dan Zou, Rose Pitstick, Jill OMoore, Janet Peters, Derek Silvius, Jasna Kriz, Walker Jackson, George A. Carlson, Eric Vallabh Minikel, Deborah E. Cabin (2023) Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease Journal of Virology, Vol. 97 Continue to DOI
Maria I. Arifin, Lech Kaczmarczyk, Doris Zeng, Samia Hannaoui, Chi Lee, Sheng Chun Chang, Gordon Mitchell, Debbie McKenzie, Michael Beekes, Walker Jackson, Sabine Gilch (2023) Heterozygosity for cervid S138N polymorphism results in subclinical CWD in gene-targeted mice and progressive inhibition of prion conversion Proceedings of the National Academy of Sciences of the United States of America, Vol. 120, Article e2221060120 Continue to DOI
Hedayat Rahin, Walker Jackson, Magnus Thordstein (2023) Effect of Transcutaneous Spinal Direct Current Stimulation in Patients with Painful Polyneuropathy and Influence of Possible Predictors of Efficacy including BDNF Polymorphism: A Randomized, Sham-Controlled Crossover Study Brain Sciences, Vol. 13, Article 229 Continue to DOI
Susanne Bauer, Chwen-Yu Chen, Maria Jonson, Lech Kaczmarczyk, Srivathsa Magadi, Walker Jackson (2023) Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntingtons disease mice Acta neuropathologica communications, Vol. 11, Article 17 Continue to DOI
Walker Jackson (2023) Etiology matters: genetic and acquired prion diseases engage different mechanisms at a presymptomatic stage Neural Regeneration Research, Vol. 18, p. 2707-2708 Continue to DOI

2022

Lech Kaczmarczyk, Melvin Schleif, Lars Dittrich, Rhiannan H. Williams, Maruša Koderman, Vikas Bansal, Ashish Rajput, Theresa Schulte, Maria Jonson, Clemens Krost, Fabio J. Testaquadra, Stefan Bonn, Walker S. Jackson (2022) Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice PLoS Pathogens, Vol. 18, Article e1010747 Continue to DOI
Susanne Bauer, Lars Dittrich, Lech Kaczmarczyk, Melvin Schleif, Rui Benfeitas, Walker Jackson (2022) Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons Life Science Alliance, Vol. 5, Article e202201530 Continue to DOI
Alana M. Thackray, Brian Lam, Erin E. McNulty, Amy V Nalls, Candace K. Mathiason, Srivathsa Magadi, Walker Jackson, Olivier Andreoletti, Cristobal Marrero-Winkens, Hermann Schätzl, Raymond Bujdoso (2022) Clearance of variant Creutzfeldt-Jakob disease prions in vivo by the Hsp70 disaggregase system Brain, Vol. 145, p. 3236-3249 Continue to DOI
Patrick Leven, Reiner Schneider, Kevin D. Siemens, Walker Jackson, Sven Wehner (2022) Application of a RiboTag-based approach to generate and analyze mRNA from enteric neural cells Neurogastroenterology and Motility, Vol. 34, Article e14309 Continue to DOI

2021

Jill R. Crittenden, Shenyu Zhai, Magdalena Sauvage, Takashi Kitsukawa, Eric Burguiere, Morgane Thomsen, Hui Zhang, Cinzia Costa, Giuseppina Martella, Veronica Ghiglieri, Barbara Picconi, Karen A. Pescatore, Ellen M. Unterwald, Walker Jackson, David E. Housman, S. Barak Caine, David Sulzer, Paolo Calabresi, Anne C. Smith, D. James Surmeier, Ann M. Graybiel (2021) CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors Neurobiology of Disease, Vol. 158, Article 105473 Continue to DOI
Lech Kaczmarczyk, Nicole Reichenbach, Nelli Blank, Maria Jonson, Lars Dittrich, Gabor C. Petzold, Walker Jackson (2021) Slc1a3-2A-CreERT2 mice reveal unique features of Bergmann glia and augment a growing collection of Cre drivers and effectors in the 129S4 genetic background Scientific Reports, Vol. 11, Article 5412 Continue to DOI

2020

Stefanie Poll, Manuel Mittag, Fabrizio Musacchio, Lena C. Justus, Eleonora Ambrad Giovannetti, Julia Steffen, Jens Wagner, Lioba Zohren, Susanne Schoch, Boris Schmidt, Walker S. Jackson, Dan Ehninger, Martin Fuhrmann (2020) Memory trace interference impairs recall in a mouse model of Alzheimer's disease Nature Neuroscience, Vol. 23, p. 952-958 Continue to DOI

2019

Lech Kaczmarczyk, Vikas Bansal, Ashish Rajput, Raza-ur Rahman, Wieslaw Krzyzak, Joachim Degen, Stefanie Poll, Martin Fuhrmann, Stefan Bonn, Walker Jackson (2019) Tagger-A Swiss army knife for multiomics to dissect cell type-specific mechanisms of gene expression in mice PLoS biology, Vol. 17, Article e3000374 Continue to DOI

2018

Cordula Rakers, Melvin Schleif, Nelli Blank, Hana Matušková, Thomas Ulas, Kristian Händler, Santiago Valle Torres, Toni Schumacher, Khalid Tai, Joachim L. Schultze, Walker S. Jackson, Gabor C. Petzold (2018) Stroke target identification guided by astrocyte transcriptome analysis Glia, Vol. 67, p. 619-633 Continue to DOI
Luise Linsenmeier, Behnam Mohammadi, Sebastian Wetzel, Berta Puig, Walker S. Jackson, Alexander Hartmann, Keiji Uchiyama, Suehiro Sakaguchi, Kristina Endres, Jörg Tatzelt, Paul Saftig, Markus Glatzel, Hermann C. Altmeppen (2018) Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein Molecular Neurodegeneration, Vol. 13, Article 18 Continue to DOI
Kan Xie, Devon P. Ryan, Brandon L. Pearson, Kristin S. Henzel, Frauke Neff, Ramon O. Vidal, Magali Hennion, Isabelle Lehmann, Melvin Schleif, Susanne Schröder, Thure Adler, Birgit Rathkolb, Jan Rozman, Anna-Lena Schütz, Cornelia Prehn, Michel E. Mickael, Marco Weiergräber, Jerzy Adamski, Dirk H. Busch, Gerhard Ehninger, Anna Matynia, Walker S. Jackson, Eckhard Wolf, Helmut Fuchs, Valerie Gailus-Durner, Stefan Bonn, Martin Hrabě de Angelis, Dan Ehninger (2018) Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, p. E2348-E2357 Continue to DOI

2017

Alana M. Thackray, Alzbeta Cardova, Hanna Wolf, Lydia Pradl, Ina Vorberg, Walker S. Jackson, Raymond Bujdoso (2017) Genetic human prion disease modelled in PrP transgenic Drosophila Biochemical Journal, Vol. 474, p. 3253-3267 Continue to DOI
Lars Dittrich, Alessandro Petese, Walker S Jackson (2017) The natural Disc1-deletion present in several inbred mouse strains does not affect sleep Scientific Reports, Vol. 7, Article 5665 Continue to DOI

Publications from other journals

2017
Alana M. Thackray, Alzbeta Cardova, Hanna Wolf, Lydia Pradl, Ina M Vorberg, Walker S. Jackson and Raymond Bujdoso
Genetic human prion disease modelled in PrP transgenic Drosophila
Biochemical Journal

2015
Walker S. Jackson and Lech Kaczmarczyk
Astonishing advances in mouse genetic tools for biomedical research
Schweizerische Medizinische Wochenschrift

Raymond Bujdoso, Matthias Landgraf, Walker S Jackson, and Alana M Thackray
Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response
World Journal of Virology

2014
Walker S. Jackson and Clemens Krost
Peculiarities of prion diseases
PLoS Pathogens

Walker S. Jackson, Clemens Krost, Andrew W. Borkowski and Lech Kaczmarczyk
Translation of the Prion Protein mRNA Is Robust in Astrocytes but Does Not Amplify during Reactive Astrocytosis in the Mouse Brain
PLoS ONE

Walker S. Jackson
Selective vulnerability to neurodegenerative disease: the curious case of Prion Protein
Disease Models & Mechanisms

2009
Walker S. Jackson, Andrew W. Borkowski, Nicki E. Watson, liver D. King, Henryk Faas, Alan Jasanoff and Susan Lindquist
Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice
Neuron

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