umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Misfolded superoxide dismutase-1 in CSF from amyotrophic lateral sclerosis patients
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
2011 (Engelska)Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 117, nr 1, s. 91-99Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Several of the superoxide dismutase-1 (SOD1) mutations linked to amyotrophic lateral sclerosis (ALS) lead to synthesis of structurally defective molecules, suggesting that any cytotoxic conformational species common for all mutations should be misfolded. SOD1 can be secreted and evidence from ALS model systems suggests that extracellular SOD1 may be involved in cytotoxicity. Three ELISAs specifically reacting with different sequence segments in misfolded SOD1 species were used for analysis of CSF from 38 neurological controls and from 96 ALS patients, 57 of whom were sporadic cases and 39 familial, including 22 patients carrying SOD1 mutations. Misfolded SOD1 was found in all samples. There were, however, no significant differences between patients with and without mutations, and between all the ALS patients and the controls. The estimated concentration of misfolded SOD1 in the interstitium of the CNS is a 1000 times lower than that required for appreciable cytotoxicity in model systems. The results argue against a direct cytotoxic role of extracellular misfolded SOD1 in ALS. Misfolded SOD1 in CSF cannot be used as a biomarker of ALS in patients with and without mutations in the enzyme.

Ort, förlag, år, upplaga, sidor
2011. Vol. 117, nr 1, s. 91-99
Nyckelord [en]
amyotrophic lateral sclerosis;biomarker;CSF;ELISA;misfolding;superoxide dismutase-1
Nationell ämneskategori
Annan klinisk medicin
Forskningsämne
klinisk kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-43892DOI: 10.1111/j.1471-4159.2011.07177.xPubMedID: 21226712OAI: oai:DiVA.org:umu-43892DiVA, id: diva2:417131
Tillgänglig från: 2011-05-16 Skapad: 2011-05-16 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis
Öppna denna publikation i ny flik eller fönster >>Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Felveckat superoxiddismutas-1 i amyotrofisk lateralskelros
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a disease in which the motor neurons die in a progressive manner, leading to paralysis and muscle wasting. ALS is always fatal, usually through respiratory failure when the disease reaches muscles needed for breathing. Most cases are sporadic, but approximately 5–10% are familial. The first gene to be linked to familial ALS encodes the antioxidant enzyme superoxide dismutase-1 (SOD1). Today, more than 160 different mutations in SOD1 have been found in ALS patients.  The mutant SOD1 proteins cause ALS by gain of a toxic property that should be common to all. Aggregates of SOD1 in motor neurons are hallmarks of ALS patients and transgenic models carrying mutant SOD1s, suggesting that misfolding, oligomerization, and aggregation of the protein may be involved in the pathogenesis. SOD1 is normally a very stable enzyme, but the structure has several components that make SOD1 sensitive to misfolding. The aim of the work in this thesis was to study misfolded SOD1 in vivo.

Small amounts of soluble misfolded SOD1 were identified as a common denominator in transgenic ALS models expressing widely different forms of mutant SOD1, as well as wild-type SOD1. The highest levels of misfolded SOD1 were found in the vulnerable spinal cord. The amounts of misfolded SOD1 were similar in all the different models and showed a broad correlation with the lifespan of the different mouse strains. The misfolded SOD1 lacked the C57-C146 intrasubunit disulfide bond and the stabilizing zinc and copper ions, and was prinsipally monomeric. Forms with higher apparent molecular weights were also found, some of which might be oligomers. Misfolding-prone monomeric SOD1 appeared to be the principal source of misfolded SOD1 in the CNS. Misfolded SOD1 in the spinal cord was found to interact mainly with chaperones, with Hsc70 being the most important. Only a minor proportion of the Hsc70 was sequestered by SOD1, however, suggesting that chaperone depletion is not involved in ALS.

 SOD1 is normally found in the cytoplasm but can be secreted. Extracellular mutant SOD1 has been found to be toxic to motor neurons and glial cells. Misfolded SOD1 in the extracellular space could be involved in the spread of the disease between different areas of the CNS and activate glial cells known to be important in ALS. The best way to study the interstitium of the CNS is through the cerebrospinal fluid (CSF), 30% of which is derived from the interstitial fluid. Antibodies specific for misfolded SOD1 were used to probe CSF from ALS patients and controls for misfolded SOD1. We did find misfolded SOD1 in CSF, but at very low levels, and there was no difference between ALS patients and controls. This argues against there being a direct toxic effect of extracellular SOD1 in ALS pathogenesis.

In conclusion, soluble misfolded SOD1 is a common denominator for transgenic ALS model mice expressing widely different mutant SOD1 proteins. The misfolded SOD1 is mainly monomeric, but also bound to chaperones, and possibly exists in oligomeric forms also. Misfolded SOD1 in the interstitium might promote spread of aggregation and activate glial cells, but it is too scarce to directly cause cytotoxicity.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2011. s. 126
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1421
Nyckelord
ALS, SOD1, protein misfolding, SOD1 conformation, disulfide-reduced, transgenic mice, cerebrospinal fluid, protein-protein interaction, antibodies
Nationell ämneskategori
Annan klinisk medicin
Forskningsämne
klinisk kemi
Identifikatorer
urn:nbn:se:umu:diva-43898 (URN)978-91-7459-215-3 (ISBN)
Disputation
2011-09-09, Hörsal Betula, Building 6M, Umeå University, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-05-20 Skapad: 2011-05-16 Senast uppdaterad: 2019-11-25Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltextPubMedExtern länk

Personposter BETA

Zetterström, PerAndersen, Peter MBrännström, ThomasMarklund, Stefan L

Sök vidare i DiVA

Av författaren/redaktören
Zetterström, PerAndersen, Peter MBrännström, ThomasMarklund, Stefan L
Av organisationen
Klinisk kemiNeurologiPatologi
I samma tidskrift
Journal of Neurochemistry
Annan klinisk medicin

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 273 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf