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Wnt and Extraocular Muscle Sparing in Amyotrophic Lateral Sclerosis
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Department of Ophthalmology and Visual Neurosciences, University of Minnesota, 6 Minneapolis, MN 55455.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
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2014 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 55, no 9, 5482-5496 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The extraocular muscles (EOM) and their motor neurons are spared in amyotrophic lateral sclerosis (ALS). In limb muscle axon retraction from the neuromuscular junctions occurs early in the disease. Wnts, a conserved family of secreted signaling molecules, play a critical role in neuromuscular junction formation. This is the first study to examine Wnt signaling for its potential involvement in maintenance of normal morphology in EOMs in ALS.

METHODS: EOM and limb muscle axons, neuromuscular junctions, and myofibers from control, aging, and ALS patients and the SOD1G93A mouse model of ALS were quantified for their expression of Wnt1, Wnt3a, Wnt5a, Wnt7a, and beta-catenin.

RESULTS: All four Wnt isoforms were expressed in most axon profiles in all human EOMs. Significantly fewer were positive for Wnt1, Wnt3a, and Wnt7a in the human limb muscles. Similar differential patterns in Wnt myofiber expression was also seen, except for Wnt7a, where expression was elevated. In the SOD1G93A mouse, all 4 Wnt isoforms were significantly decreased in the neuromuscular junctions at the terminal stage compared to age matched controls. Beta-catenin was activated in a subset of myofibers in EOM and limb muscle in all patients.

CONCLUSIONS: The differences in Wnt expression in EOM and limb muscle, particularly at the neuromuscular junction level, suggest that they play a role in the pathophysiology of ALS. Collectively, the data support a role for Wnt signaling in the preservation of the EOM in ALS and their dysregulation and the subsequent development of pathology in the ALS limb muscles.

Place, publisher, year, edition, pages
ARVO, The Association for Reserach in Vision and Ophthalmology , 2014. Vol. 55, no 9, 5482-5496 p.
Keyword [en]
extraocular muscles, Wnt, neuromuscular junctions, amyotrophic lateral sclerosis, beta-catenin, skeletal muscle, SOD1(G93A) mice
National Category
Ophthalmology
Identifiers
URN: urn:nbn:se:umu:diva-91978DOI: 10.1167/iovs.14-14886ISI: 000343146900003PubMedID: 25125606OAI: oai:DiVA.org:umu-91978DiVA: diva2:739077
Available from: 2014-08-20 Created: 2014-08-20 Last updated: 2017-05-11Bibliographically 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)
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Available from: 2016-05-18 Created: 2016-05-11 Last updated: 2017-04-05Bibliographically approved

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