umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Unchanged neurotrophic factors and their receptors correlate with sparing in extraocular muscles in amyotrophic lateral sclerosis
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
Show others and affiliations
2016 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 15, 6831-6842 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: To investigate the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the distribution of neurotrophic factors (NTFs) and their receptors in EOMs and limb muscles from ALS transgenic mice.

Methods: Muscle samples collected from transgenic mice overexpressing human superoxide dismutase type 1 mutations (SOD1G93A, the most widely used mouse model of ALS) at 50 and 150 days as well as age-matched controls were analyzed with immunohistochemistry using antibodies against brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and the neurotrophin receptors p75NTR, tyrosine kinase (Trk) receptor TrkB and TrkC, and GDNF family receptor alpha-1 (GFRα-1).

Results: There was an intrinsic difference in NTF expression between EOMs and limb muscles in control mice: EOMs presented significantly lower number of neuromuscular junctions (NMJs) labeled for BDNF and NT-4 at 50 days, and for BDNF and GDNF at 150 days, compared with the control limb muscles of corresponding age. In ALS transgenic mice at 150 days, NTF expression in limb muscles was significantly changed but not in EOMs: the limb muscles presented a significant decline in the number of NMJs labeled for BDNF, NT-4, GDNF, p75NTR, TrkB, and TrkC, which was not observed in EOMs.

Conclusions: The significant differences in expression of NTFs on NMJs between EOMs and limb muscles in both control and ALS transgenic mice suggest that NTF may be involved in the pathogenesis of ALS and the resistance of EOMs to the disease.

Place, publisher, year, edition, pages
Rockville: The association for research in vision and ophthalmology , 2016. Vol. 57, no 15, 6831-6842 p.
Keyword [en]
extraocular muscles, neuromuscular junctions, neurotrophin, amyotrophic lateral sclerosis, neurotrophic factor
National Category
Neurosciences
Research subject
Human Anatomy
Identifiers
URN: urn:nbn:se:umu:diva-129395DOI: 10.1167/iovs.16-20074ISI: 000392929500045PubMedID: 28002846Scopus ID: 2-s2.0-85007286240OAI: oai:DiVA.org:umu-129395DiVA: diva2:1059852
Available from: 2016-12-25 Created: 2016-12-25 Last updated: 2017-04-05Bibliographically approved
In thesis
1. A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis: Differences between extraocular and limb muscles
Open this publication in new window or tab >>A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis: Differences between extraocular and limb muscles
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder. ALS has been traditionally believed to be primarily a motor neuron disease. However, accumulating data indicate that loss of contact between the axons and the muscle fibres occurs early; long before the death of motor neurons and that muscle fibres may initiate motor neuron degeneration. Thus, the view of ALS is changing focus from motor neurons alone to also include the muscle fibres and the neuromuscular junctions (NMJs). While skeletal muscles are affected in ALS, oculomotor disturbances are not dominant features of this disease and extraocular muscles (EOMs) are far less affected than limb muscles. Why oculomotor neurons and EOMs are capable to be more resistant in the pathogenetic process of ALS is still unknown.

The overall goal of this thesis is to explore the pathophysiology of ALS from a muscle perspective and in particular study the expression and distribution of key neurotrophic factors (NTFs) and Wnt proteins in EOMs and limb muscles from ALS donors and from SOD1G93A transgenic mice. Comparisons were made with age-matched controls to distinguish between changes related to ALS and to ageing.

Results: Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4) were present in EOMs and limb muscles at both mRNA and protein levels in control mice. The mRNA levels of BDNF, NT-3 and NT-4 were significantly lower in EOMs than in limb muscles of early and/or late control mice, indicating an intrinsic difference in NTFs expression between EOMs and limb muscles. qRT-PCR analysis showed significantly upregulated mRNA levels of NT-3 and GDNF in EOMs but significantly downregulated mRNA levels of NT-4 in limb muscles from SOD1G93A transgenic mice at early stage. The NTFs were detected immunohistochemically in NMJs, nerve axons and muscle fibres. The expression of BDNF, GDNF and NT-4 on NMJs of limb muscles, but not of EOMs, was significantly decreased in terminal stage ALS animals as compared to the limb muscles of the age-matched controls. In contrast, NTFs expression in intramuscular nerve axons did not present significant changes in either muscle group of early or late ALS mice. NTFs, especially BDNF and NT-4 were upregulated in some small-sized muscle fibres in limb muscles of late stage ALS mice. All the four Wnt isoforms, Wnt1, Wnt3a, Wnt5a and Wnt7a were detected in most axon profiles in all human EOMs with ALS, whereas significantly fewer axon profiles were positive in the human limb muscles except for Wnt5a. Similar differential patterns were found in myofibres, except for Wnt7a, where its expression was elevated within sarcolemma of limb muscle fibres. β-catenin, a marker of the canonical Wnt pathway was activated in a subset of myofibres in the EOMs and limb muscle in all ALS patients. In the SOD1G93A mouse, all four Wnt isoforms were significantly decreased in the NMJs at the terminal stage compared to age matched controls.

Conclusions: There were clear differences in NTF and Wnt expression patterns between EOM and limb muscle, suggesting that they may play a role in the distinct susceptibility of these two muscle groups to ALS. In particular, the early upregulation of GDNF and NT-3 in the EOMs might play a role in the preservation of the EOMs in ALS. Further studies are needed to determine whether these proteins and the pathways they control may be have a future potential as protecting agents for other muscles.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. 92 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1803
Keyword
Neuromuscular junctions, Extraocular muscles, Skeletal muscle, Neurotrophic factor, Wnt, Motor neuron disease, Amyotrophic lateral sclerosis, SOD1G93A mice
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-120219 (URN)978-91-7601-445-5 (ISBN)
Public defence
2016-06-08, KB3B1 (149), KBC-huset, KBC house, Umeå University, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-05-18 Created: 2016-05-11 Last updated: 2017-04-05Bibliographically approved

Open Access in DiVA

fulltext(1283 kB)28 downloads
File information
File name FULLTEXT01.pdfFile size 1283 kBChecksum SHA-512
1258b761c434898c62d2eb1ac3bfb0ccddc7c79b128f272b5ee55a975dee2efa05e4d74ebfcbc440dc2510a17ade9b41b78625798fb927040cf0ffd59ade1513
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMedScopus

Search in DiVA

By author/editor
Harandi, Vahid MGaied, Aida RNBrännström, ThomasPedrosa-Domellöf, FatimaLiu, Jing-Xia
By organisation
AnatomyOphthalmologyPathology
In the same journal
Investigative Ophthalmology and Visual Science
Neurosciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 28 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 275 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf