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
Show/Hide content

Open positions
Show/Hide content

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
Show/Hide content

Publications from DiVA

2019

2017

2016

2013

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

Online resources
Show/Hide content

Research area
Show/Hide content

Organisation
Show/Hide content