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Dissection of Single Skeletal Muscle Fibers for Immunofluorescent and Morphometric Analyses of Whole-Mount Neuromuscular Junctions
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ALS-Associated Endoplasmic Reticulum Proteins in Denervated Skeletal Muscle: Implications for Motor Neuron Disease
C M Jesse1,2, E Bushuven1, P Tripathi1
1Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
Brain Pathology (Zurich, Switzerland)
|October 30, 2016
Summary
Endoplasmic reticulum (ER) protein alterations in muscle fibers are linked to neurogenic muscular atrophies (NMAs) like amyotrophic lateral sclerosis (ALS). Increased ER chaperones and autophagy markers in denervated muscle suggest a protective response, potentially implicating ER pathology in motor neuron diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Muscle Physiology
Background:
- Alpha-motoneurons and muscle fibers are interdependent, relying on endoplasmic reticulum (ER) function.
- Mutations in ER proteins like VAPB, SigR1, and HSP27 are associated with hereditary motor neuron diseases (MNDs).
Purpose of the Study:
- To investigate the expression and localization of ER proteins (VAPB, SigR1, HSP27) and autophagy markers in muscle tissue from patients with amyotrophic lateral sclerosis (ALS) and other neurogenic muscular atrophies (NMAs).
- To compare these patterns in human tissues with mouse models of neurogenic muscular atrophy.
Main Methods:
- Immunohistochemistry and immunoblotting were used on biopsy and autopsy muscle tissue from human patients and mouse models.
- Analysis focused on the expression and localization of VAPB, chaperones, and autophagy markers in relation to denervation and muscle pathology.
Main Results:
- VAPB staining decreased at neuromuscular junctions in denervated mouse muscle.
- Extrasynaptic VAPB levels, chaperones, and autophagy markers increased in denervated muscle fibers of patients with MNDs/NMAs, particularly at sites of myofibrillar disintegration.
- Similar patterns were observed in G93A-SOD1 mouse models, with additional evidence of myopathic changes like globular VAPB structures and misfolded SOD1.
Conclusions:
- Altered expression and localization of ER proteins and autophagy markers represent a dynamic muscle fiber response to denervation.
- The endoplasmic reticulum is vulnerable in both muscle fibers and alpha-motoneurons.
- ER pathology may contribute to selective degenerative changes in the neuromuscular axis in MNDs.
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