ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease

Moloney, Elizabeth B.; Winter, Fred de; Verhaagen, Joost

doi:10.3389/fnins.2014.00252

Cited by 263 publications

(248 citation statements)

References 233 publications

(302 reference statements)

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“…Thus, we believe that surface transplantation is a less invasive technique that could have more widespread application to the nervous system. In amyotrophic lateral sclerosis (ALS), anterior horn cells and axons often degenerate (51). Suitable donor cells applied on the surface of degenerated anterior roots of the spinal cord could provide a minimally invasive method of cell transplantation to restore lost function of the motor neurons.…”

Section: Discussionmentioning

confidence: 99%

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

Sekiya

Holley

Hashido

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cell transplantation therapy has long been investigated as a therapeutic intervention for neurodegenerative disorders, including spinal cord injury, Parkinson’s disease, and amyotrophic lateral sclerosis. Indeed, patients have high hopes for a cell-based therapy. However, there are numerous practical challenges for clinical translation. One major problem is that only very low numbers of donor cells survive and achieve functional integration into the host. Glial scar tissue in chronic neurodegenerative disorders strongly inhibits regeneration, and this inhibition must be overcome to accomplish successful cell transplantation. Intraneural cell transplantation is considered to be the best way to deliver cells to the host. We questioned this view with experiments in vivo on a rat glial scar model of the auditory system. Our results show that intraneural transplantation to the auditory nerve, preceded by chondroitinase ABC (ChABC)-treatment, is ineffective. There is no functional recovery, and almost all transplanted cells die within a few weeks. However, when donor cells are placed on the surface of a ChABC-treated gliotic auditory nerve, they autonomously migrate into it and recapitulate glia- and neuron-guided cell migration modes to repair the auditory pathway and recover auditory function. Surface transplantation may thus pave the way for improved functional integration of donor cells into host tissue, providing a less invasive approach to rescue clinically important neural tracts.

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Section: Discussionmentioning

confidence: 99%

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

Sekiya

Holley

Hashido

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Taken Amyotrophic lateral sclerosis (ALS) 1 is an adult-onset progressive neurodegenerative disease that targets both upper and lower motor neurons via an unknown mechanism, leading to paralysis and eventually death. Pathological changes affecting synapses in both the primary motor cortex and the peripheral neuromuscular junctions (NMJs) are considered an early occurrence in ALS, often preceding the degeneration of the axons and clinical symptomatic onset (1). Although synapse disruption is common to many neurodegenerative diseases and the molecular mechanisms underlying synapse stabilization and maintenance are of keen interest, the exact mechanisms governing synapse disruption have yet to be understood.…”

Section: A315tmentioning

confidence: 99%

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

Gershoni-Emek

Mazza

Chein

et al. 2016

Molecular & Cellular Proteomics

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Synapse disruption takes place in many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the mechanistic understanding of this process is still limited. We set out to study a possible role for dynein in synapse integrity. Cytoplasmic dynein is a multisubunit intracellular molecule responsible for diverse cellular functions, including long-distance transport of vesicles, organelles, and signaling factors toward the cell center. A less well-characterized role dynein may play is the spatial clustering and anchoring of various factors including mRNAs in distinct cellular domains such as the neuronal synapse. Here, in order to gain insight into dynein functions in synapse integrity and disruption, we performed a screen for novel dynein interactors at the synapse. Dynein immunoprecipitation from synaptic fractions of the ALS model mSOD1 G93A and wild-type controls, followed by mass spectrometry analysis on synaptic fractions of the ALS model mSOD1 G93A and wild-type controls, was performed. Using advanced network analysis, we identified Staufen1, an RNA-binding protein required for the transport and localization of neuronal RNAs, as a major mediator of dynein interactions via its interaction with protein phosphatase 1-beta (PP1B). Both in vitro and in vivo validation assays demonstrate the interactions of Staufen1 and PP1B with dynein, and their colocalization with synaptic markers was altered as a result of two separate ALS-linked mutations: mSOD1 G93A and TDP43 A315T. Taken together, we suggest a model in which dynein's interaction with Staufen1 regulates mRNA localization along the axon and the synapses, and alterations in this process may correlate with synapse disruption and ALS toxicity. Molecular & Cellular

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“…Motor neuron damage or perturbation of nervemuscle signaling through disruption of the NMJ causes a variety of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and hereditary spastic paraplegia (HSP) (2)(3)(4)(5)(6). These neurodegenerative diseases are genetically heterogeneous, with mutations in proteins associated with diverse cellular and molecular functions (7)(8)(9)(10).…”

mentioning

confidence: 99%

Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106

Anderson

Cannavino

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Innervation of skeletal muscle by motor neurons occurs through the neuromuscular junction, a cholinergic synapse essential for normal muscle growth and function. Defects in nerve-muscle signaling cause a variety of neuromuscular disorders with features of ataxia, paralysis, skeletal muscle wasting, and degeneration. Here we show that the nuclear zinc finger protein ZFP106 is highly enriched in skeletal muscle and is required for postnatal maintenance of myofiber innervation by motor neurons. Genetic disruption of Zfp106 in mice results in progressive ataxia and hindlimb paralysis associated with motor neuron degeneration, severe muscle wasting, and premature death by 6 mo of age. We show that ZFP106 is an RNA-binding protein that associates with the core splicing factor RNA binding motif protein 39 (RBM39) and localizes to nuclear speckles adjacent to spliceosomes. Upon inhibition of pre-mRNA synthesis, ZFP106 translocates with other splicing factors to the nucleolus. Muscle and spinal cord of Zfp106 knockout mice displayed a gene expression signature of neuromuscular degeneration. Strikingly, altered splicing of the Nogo (Rtn4) gene locus in skeletal muscle of Zfp106 knockout mice resulted in ectopic expression of NOGO-A, the neurite outgrowth factor that inhibits nerve regeneration and destabilizes neuromuscular junctions. These findings reveal a central role for Zfp106 in the maintenance of nerve-muscle signaling, and highlight the involvement of aberrant RNA processing in neuromuscular disease pathogenesis.ZNF106 | amyotrophic lateral sclerosis (ALS) | neuromuscular junction (NMJ) | motor neuron disease (MND) | pre-mRNA splicing S ignaling between the presynaptic terminus of a motor neuron and the postsynaptic membrane of a skeletal myofiber occurs at the neuromuscular junction (NMJ), the site of communication that allows for neural control of myofiber identity, growth, and contractility (1). Motor neuron damage or perturbation of nervemuscle signaling through disruption of the NMJ causes a variety of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and hereditary spastic paraplegia (HSP) (2-6). These neurodegenerative diseases are genetically heterogeneous, with mutations in proteins associated with diverse cellular and molecular functions (7)(8)(9)(10). Although the precise disease mechanisms underlying the pathogenesis of these disorders remain unclear, abnormalities in apoptotic signaling, oxidative stress, protein folding, and RNA processing in motor neurons and skeletal muscle have been implicated in these diseases (11)(12)(13)(14)(15).In a bioinformatics screen for nuclear proteins with enriched expression in skeletal muscle, we identified ZFP106, a zinc finger protein first characterized as an immunodominant cytotoxic determinant of the mouse H3 minor histocompatibility complex (16,17). Zinc fingers (ZnFs) mediate DNA, RNA, and protein interactions and are commonly found in regulatory proteins that govern gen...

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ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease

Cited by 263 publications

References 233 publications

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106

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