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Unchanged Neurotrophic Factors and Their Receptors with Sparing in Extraocular Muscles in Amyotrophic Lateral Sclerosis
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. (Muscle group)ORCID iD: 0000-0001-9255-0517
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.
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(English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783Article, review/survey (Other academic) Submitted
Abstract [en]

PURPOSE. In a recent study on an amyotrophic lateral sclerosis (ALS) mouse model, we reported significant differences in mRNA levels of several neurotrophic factors (NTFs) between extraocular muscles (EOMs) and limb muscles. In order to further evaluate the possible role of NTF in the pathogenesis of ALS, we examined the distribution of the NTFs and their receptors in EOMs and limb muscles of early and late stages of SOD1G93A ALS mice.

METHODS. EOMs and limb muscles from control and ALS transgenic mice (SOD1G93A ) at early and late stages were analysed for the distribution of four different NTFs (BDNF, GDNF, NT-3, and NT-4) and their receptors (TrkB, TrkC, p75NTR, and GFR-α1) using immunohistochemistry. Labelling with NTFs at NMJs was quantified and compared between EOMs and limb muscles, and between control and SOD1G93A ALS mice.

RESULTS. NTFs and their receptors were detected in several structures in both muscle groups, including neuromuscular junctions (NMJs), intramuscular nerve axons and muscle fibres of both control and SOD1G93A ALS mice. In control mice, EOMs had lower percentage of NMJs labelled for BDNF and NT-4 at 50 days, and for BDNF, GDNF and NT-3 at 150 days, in comparison to limb muscles. In ALS mice, the percentage of NMJs labelled for BDNF, GDNF and NT-4, as well as for the receptors TrkB, TrkC, p75NTR and GFR-α1was significantly downregulated in limb muscles, but not in EOMs from early or late stage. In limb muscles from late ALS mice, the four NTFs showed no changes in intramuscular nerve axons whereas BDNF and NT-4 were increased in a number of small sized muscle fibres.

CONCLUSIONS. The significant difference in NTFs between EOMs and limb muscles in both control and ALS transgenic ALS mice, suggests that NTF are closely associated with the pathogenesis of ALS and the resistance of EOMs to the disease.

Place, publisher, year, edition, pages
Umea.
Keyword [en]
neurotrophins, neurotrophic factor, extraocular muscles, ALS, nerve axons, neuromuscular junctions, 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: urn:nbn:se:umu:diva-120218OAI: oai:DiVA.org:umu-120218DiVA: diva2:927245
Available from: 2016-05-11 Created: 2016-05-11 Last updated: 2016-05-16
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: 2016-05-26Bibliographically approved

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