title: ALS-Associated Endoplasmic Reticulum Proteins in Denervated Skeletal Muscle: Implications for Motor Neuron Disease Pathology.
abstract: Alpha-motoneurons and muscle fibres are structurally and functionally interdependent. Both cell types particularly rely on endoplasmic reticulum (ER/SR) functions. Mutations of the ER proteins VAPB, SigR1 and HSP27 lead to hereditary motor neuron diseases (MNDs). Here, we determined the expression profile and localization of these ER proteins/chaperons by immunohistochemistry and immunoblotting in biopsy and autopsy muscle tissue of patients with amyotrophic lateral sclerosis (ALS) and other neurogenic muscular atrophies (NMAs) and compared these patterns to mouse models of neurogenic muscular atrophy. Postsynaptic neuromuscular junction staining for VAPB was intense in normal human and mouse muscle and decreased in denervated Nmd2Jmouse muscle fibres. In contrast, VAPB levels together with other chaperones and autophagy markers were increased in extrasynaptic regions of denervated muscle fibres of patients with MNDs and other NMAs, especially at sites of focal myofibrillar disintegration (targets). These findings did not differ between NMAs due to ALS and other causes. G93A-SOD1 mouse muscle fibres showed a similar pattern of protein level increases in denervated muscle fibres. In addition, they showed globular VAPB-immunoreactive structures together with misfolded SOD1 protein accumulations, suggesting a primary myopathic change. Our findings indicate that altered expression and localization of these ER proteins and autophagy markers are part of the dynamic response of muscle fibres to denervation. The ER is particularly prominent and vulnerable in both muscle fibres and alpha-motoneurons. Thus, ER pathology could contribute to the selective build-up of degenerative changes in the neuromuscular axis in MNDs.
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.|Department of Neurosurgery, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: C M
authors: CM
authors: Jesse
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: E
authors: E
authors: Bushuven
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: P
authors: P
authors: Tripathi
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.|Department of Neurology, Ulm University, Helmholtzstr 8/2, Ulm, 89081, Germany.
authors: A
authors: A
authors: Chandrasekar
authors: Institute of Clinical Neurobiology, University of Würzburg, Versbacherstr. 5, Würzburg, 97078, Germany.|Columbia University Medical Center, Center for Motor Neuron Biology and Disease, 630 West 168th Street, New York, NY, 10032.
authors: C M
authors: CM
authors: Simon
authors: Institute of Clinical Neurobiology, University of Würzburg, Versbacherstr. 5, Würzburg, 97078, Germany.|Department of Child and Adolescent Psychiatry, University Hospital Würzburg, Füchsleinstr. 15, Würzburg, 97080, Germany.
authors: C
authors: C
authors: Drepper
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: A
authors: A
authors: Yamoah
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: A
authors: A
authors: Dreser
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: I
authors: I
authors: Katona
authors: Institute of Neuroanatomy, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: S
authors: S
authors: Johann
authors: Institute of Neuroanatomy, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: C
authors: C
authors: Beyer
authors: Department of Neurology, District Hospital Siegen, Siegen, 57076, Germany.
authors: S
authors: S
authors: Wagner
authors: Department of Neurology, District Hospital Siegen, Siegen, 57076, Germany.
authors: M
authors: M
authors: Grond
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: S
authors: S
authors: Nikolin
authors: Academic Medical Centre, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.
authors: J
authors: J
authors: Anink
authors: Academic Medical Centre, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.
authors: D
authors: D
authors: Troost
authors: Institute of Clinical Neurobiology, University of Würzburg, Versbacherstr. 5, Würzburg, 97078, Germany.
authors: M
authors: M
authors: Sendtner
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: A
authors: A
authors: Goswami
authors: Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: J
authors: J
authors: Weis
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology; D000818:Animals; D001344:Autopsy; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000473:pathology*; D009046:Motor Neurons / Q000378:metabolism; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000473:pathology; D009469:Neuromuscular Junction; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000502:physiology
chemical_list: D008565:Membrane Proteins; C496748:VAPB protein, human; C529892:VAPB protein, mouse; D033921:Vesicular Transport Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ALS; ER chaperones; Motor neuron disease (MND); Neurogenic muscular atrophy (NMA); Neuromuscular junction (NMJ); Sigma Receptor 1 (SigR1); VAPB