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A peripheral immune response in Huntington's disease and delineation of its importance in disease pathology

Magnusson-Lind, Anna LU (2014) In Faculty of Medicine Doctoral Dissertation Series 48.
Abstract (Swedish)
Popular Abstract in Swedish

Huntingtons sjukdom (HS) är en ärftlig hjärnsjukdom utan botemedel. Den orsakas av en mutation i en gen som kallas huntingtin. Den klassas som en s.k. neurodegenerativ sjukdom, där man ser en förlust av neuroner i delar av hjärnan som kontrollerar kroppsrörelser. Detta resulterar i dansliknande rörelser (chorea) och det är även därför som HS ibland kallas för danssjukan. Traditionellt sett har forskningen kring HS fokuserat kring vad som händer i hjärnan och vad som orsakar neurodegeneration. Det finns dock andra symptom som inte kan förbises, patienter lider av viktminskning, trots normalt intag av näring. De lider också av förtvining av muskler, försämring av kognitiv förmåga, psykiatriska... (More)
Popular Abstract in Swedish

Huntingtons sjukdom (HS) är en ärftlig hjärnsjukdom utan botemedel. Den orsakas av en mutation i en gen som kallas huntingtin. Den klassas som en s.k. neurodegenerativ sjukdom, där man ser en förlust av neuroner i delar av hjärnan som kontrollerar kroppsrörelser. Detta resulterar i dansliknande rörelser (chorea) och det är även därför som HS ibland kallas för danssjukan. Traditionellt sett har forskningen kring HS fokuserat kring vad som händer i hjärnan och vad som orsakar neurodegeneration. Det finns dock andra symptom som inte kan förbises, patienter lider av viktminskning, trots normalt intag av näring. De lider också av förtvining av muskler, försämring av kognitiv förmåga, psykiatriska problem, sömnsvårigheter, hjärtsvikt och en subtil ökning av inflammatoriska proteiner. Dessa symptom kan påverka både livskvaliteten samt hur sjukdomen framskrider.

Det övergripande syftet med denna avhandling var att undersöka mekanismen bakom förhöjda inflammatoriska proteiner som tidigare detekterats i patienter med HS och hur dessa skulle kunna påverka andra aspekter av sjukdomen, såsom muskelförtvining.

Vi isolerade celler tillhörande immunförsvaret, från både patienter med HS och från tre olika musmodeller av HS, och studerade deras aktivitet samt funktion. Dessa studier ledde oss fram till att vidare studera intracellulära signaleringsvägar involverade i immunaktivering av celler. Vi ville också undersöka genuttryck i skelettmuskelvävnad från en musmodell av HS och också ta reda på om och hur inflammatoriska proteiner skulle kunna påverka muskelceller i kultur.

Våra studier av immuncellaktivering, visade att immune celler från både HS patienter och musmodellerna producerar högre nivåer av inflammatoriska proteiner efter aktivering. Detta verkar bero på en direkt interaktion mellan muterat huntingtin och en signaleringsväg som heter NFκB. Vi kunde också se förändringar i uttryck av gener involverade i muskelkontraktion och immunförsvaret i skelettmuskel. Genom att i kultur stimulera muskelceller, med inflammatoriska proteiner som tidigare visats förhöjda i HS, kunde vi vidare se en förändring i dessa gener.

De sammanhängande resultaten av den här avhandlingen borgar för fortsatta studier av immunförsvaret i HS och hur det kan påverka sjukdomen. Resultaten stödjer också framtida studier av anti-inflammatorisk behandling av HS. (Less)
Abstract
Huntington’s disease (HD) is a fatal, hereditary disease for which there is no cure. It is caused by a mutation in a gene called huntingtin. HD is a so-called neurodegenerative disease, where there is a loss of neurons in areas of the brain that control body movements. This results in uncontrolled dance-like movements (chorea). Traditionally, research on HD has focused round the brain and what is causing the neurodegeneration. There are however other symptoms that cannot be overlooked. Patients are suffering from weight loss despite adequate intake of nutrition. They also suffer from muscle wasting, cognitive deterioration, psychiatric problems, sleep disturbances, cardiac failure and a subtle increase in inflammatory proteins. These... (More)
Huntington’s disease (HD) is a fatal, hereditary disease for which there is no cure. It is caused by a mutation in a gene called huntingtin. HD is a so-called neurodegenerative disease, where there is a loss of neurons in areas of the brain that control body movements. This results in uncontrolled dance-like movements (chorea). Traditionally, research on HD has focused round the brain and what is causing the neurodegeneration. There are however other symptoms that cannot be overlooked. Patients are suffering from weight loss despite adequate intake of nutrition. They also suffer from muscle wasting, cognitive deterioration, psychiatric problems, sleep disturbances, cardiac failure and a subtle increase in inflammatory proteins. These symptoms further affect the quality of life and disease progression for patients with HD.

The overall aim of this thesis was to investigate the mechanism behind elevated levels of inflammatory proteins previously detected in HD patients, and how that could affect other aspects of disease pathology, such as muscle wasting.

We isolated cells of the immune response, from both HD patients and three different mouse models of HD, and studied their activity as well as function. These studies led us to further investigate intracellular signaling pathways involved in immune cell-function. We also wanted to investigate gene expression in skeletal muscle from a mouse model of HD and to investigate if and how inflammatory proteins could affect muscle cells in culture.

Our studies of immune cell-activation showed that immune cells from both HD patients and from three different mouse models of HD produce higher levels of inflammatory proteins when activation is triggered. This seems to be caused by the direct interaction of the mutant huntingtin protein with a signaling pathway called NFκB. We could also see that there are changes in the expression of genes involved in muscle contraction and the immune response in skeletal muscle, and by stimulating muscle cells in culture with inflammatory proteins known to be elevated in HD, we could furthermore see a change in these genes.

The results of this thesis warrants for further investigations into the inflammatory response in HD and how it may affect the disease. The findings also support future studies of anti-inflammatory treatment in HD. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Dr Weydt, Patrick, Klinik für Neurologie, Ulm University, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Huntington's disease, peripheral symptoms, immune response, muscle atrophy, cytokines, gene expression, JAK/STAT, NFkB, IL-6, TNF-alpha
in
Faculty of Medicine Doctoral Dissertation Series
volume
48
pages
182 pages
publisher
Lund University (Media-Tryck)
defense location
Segerfalksalen, BMC A10, Lund
defense date
2014-04-26 09:30
ISSN
1652-8220
ISBN
978-91-87651-74-8
language
English
LU publication?
yes
id
ed5d9b66-7ae0-437c-a275-fb25f20a9dd5 (old id 4391181)
date added to LUP
2014-04-08 12:44:47
date last changed
2016-09-19 08:44:45
@phdthesis{ed5d9b66-7ae0-437c-a275-fb25f20a9dd5,
  abstract     = {Huntington’s disease (HD) is a fatal, hereditary disease for which there is no cure. It is caused by a mutation in a gene called huntingtin. HD is a so-called neurodegenerative disease, where there is a loss of neurons in areas of the brain that control body movements. This results in uncontrolled dance-like movements (chorea). Traditionally, research on HD has focused round the brain and what is causing the neurodegeneration. There are however other symptoms that cannot be overlooked. Patients are suffering from weight loss despite adequate intake of nutrition. They also suffer from muscle wasting, cognitive deterioration, psychiatric problems, sleep disturbances, cardiac failure and a subtle increase in inflammatory proteins. These symptoms further affect the quality of life and disease progression for patients with HD. <br/><br>
The overall aim of this thesis was to investigate the mechanism behind elevated levels of inflammatory proteins previously detected in HD patients, and how that could affect other aspects of disease pathology, such as muscle wasting.<br/><br>
We isolated cells of the immune response, from both HD patients and three different mouse models of HD, and studied their activity as well as function. These studies led us to further investigate intracellular signaling pathways involved in immune cell-function. We also wanted to investigate gene expression in skeletal muscle from a mouse model of HD and to investigate if and how inflammatory proteins could affect muscle cells in culture.<br/><br>
Our studies of immune cell-activation showed that immune cells from both HD patients and from three different mouse models of HD produce higher levels of inflammatory proteins when activation is triggered. This seems to be caused by the direct interaction of the mutant huntingtin protein with a signaling pathway called NFκB. We could also see that there are changes in the expression of genes involved in muscle contraction and the immune response in skeletal muscle, and by stimulating muscle cells in culture with inflammatory proteins known to be elevated in HD, we could furthermore see a change in these genes.<br/><br>
The results of this thesis warrants for further investigations into the inflammatory response in HD and how it may affect the disease. The findings also support future studies of anti-inflammatory treatment in HD.},
  author       = {Magnusson-Lind, Anna},
  isbn         = {978-91-87651-74-8},
  issn         = {1652-8220},
  keyword      = {Huntington's disease,peripheral symptoms,immune response,muscle atrophy,cytokines,gene expression,JAK/STAT,NFkB,IL-6,TNF-alpha},
  language     = {eng},
  pages        = {182},
  publisher    = {Lund University (Media-Tryck)},
  school       = {Lund University},
  series       = {Faculty of Medicine Doctoral Dissertation Series},
  title        = {A peripheral immune response in Huntington's disease and delineation of its importance in disease pathology},
  volume       = {48},
  year         = {2014},
}