The “Dying-Back” Phenomenon of Motor Neurons in ALS

Dadon-Nachum, Michal; Melamed, Eldad; Offen, Daniel

doi:10.1007/s12031-010-9467-1

Cited by 344 publications

(309 citation statements)

References 55 publications

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“…Pertinent to this, the »dying back« pattern has been proposed (27). Our results imply that mutant SOD1 may provoke mechanical damage to the muscles and neuromuscular junctions indirectly, by being unable to perform the relaxing function of the WT.…”

Section: Resultssupporting

confidence: 66%

The Effects of Human Wild-Type and Fals Mutant L144P SOD1 on Non-Vascular Smooth Muscle Contractions / EFEKTI HUMANE NORMALNE I FALS MUTIRANE L144P SOD1 NA NEVASKULARNE KONTRAKCIJE GLATKIH MIŠIĆA

Nikolić‐Kokić¹,

Oreščanin-Dušić²,

Slavić³

et al. 2013

Journal of Medical Biochemistry

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SummaryBackground: Mutated copper, zinc-containing superoxide dismutase (SOD1) may self-aggregate, an event that could also be an initial cause of motor neuron malfunction leading to disease onset. The effects of human mutated SOD1 protein from the blood of familial amyotrophic lateral sclerosis (FALS) patients bearing Leu144Phe (L144F) mutation were compared to wild-type (WT) human SOD1 derived from healthy examinees, for enzymatic activity and the effects on isometric contractions of non-vascular smooth muscle. Methods: We isolated WT and L144F SOD1 enzymes from eight patients with FALS, L144F mutation in exon 5 and eight healthy controls. We then investigated SOD1 activities in the obtained samples by the adrenaline method and profiled them electrophoretically. Finally, we applied WT and L144F SOD1 on the isolated rat uterus. Results: L144F SOD1 showed lower superoxide-dismutating activity compared to WT human SOD1. We found that, in contrast to WT human SOD1, mutated L144F does not induce smooth muscle relaxation. Conclusions: Our data suggest that the lack of relaxation of muscle tonus in the presence of mutated SOD1 may have pathogenic feedback effects in FALS.

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Section: Resultssupporting

confidence: 66%

The Effects of Human Wild-Type and Fals Mutant L144P SOD1 on Non-Vascular Smooth Muscle Contractions / EFEKTI HUMANE NORMALNE I FALS MUTIRANE L144P SOD1 NA NEVASKULARNE KONTRAKCIJE GLATKIH MIŠIĆA

Nikolić‐Kokić¹,

Oreščanin-Dušić²,

Slavić³

et al. 2013

Journal of Medical Biochemistry

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“…The Drosophila orthologue, dSarm, was identified from a forward genetic screen for mutations that promoted long-term survival of severed axons, and this protective activity was also observed in mice with a knockout allele for Sarm1 42,43 . These data suggest that TIR-1/Sarm1 may actively participate in a cell death programme targeting damaged axons, which may be relevant to the axon 'dying back' phenotype observed in neurodegenerative diseases including ALS 44 . Furthermore, tir-1 has been linked to a non-apoptotic cell death pathway supporting our observations about ced-3/Caspase-3-independent mechanisms regulating TDP-43 toxicity in our C. elegans ALS models 8 .…”

Section: Discussionmentioning

confidence: 85%

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

Vérièpe

Fossouo²,

Parker

2015

Nat Commun

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease thought to employ cell non-autonomous mechanisms where neuronal injury engages immune responses to influence disease progression. Here we show that the expression of mutant proteins causative for ALS in Caenorhabditis elegans motor neurons induces an innate immune response via TIR-1/Sarm1. Loss of function mutations in tir-1, associated downstream kinases, and the transcription factor atf-7 all suppress motor neuron degeneration. The neurosecretory proteins UNC-13 and UNC-31 are required for induction of the immune response as well as the degeneration of motor neurons. The human orthologue of UNC-13, UNC13A, has been identified as a genetic modifier of survival in ALS, and we provide functional evidence of UNC-13/UNC13A in regulating motor neuron degeneration. We propose that the innate immune system reacts to the presence of mutant proteins as a contagion, recruiting a pathogen resistance response that is ultimately harmful and drives progressive neurodegeneration.

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“…and that skeletal muscle directly contributes to ALS pathogenesis (1,4,5), the so-called "dying-back model. "…”

Section: Discussionmentioning

confidence: 99%

“…The hallmark of the pathology is the selective death of upper and/or lower motor neurons, but several researchers point out that muscle denervation precedes neuronal death in mouse models of the pathology, according to the so-called "dying back" model of neuronal death (3,4). It has been proposed that muscle actively contributes to motor neuron degeneration, possibly by releasing factors that inhibit neurite outgrowth (5,6).…”

Section: Voltage-clamp | Patch-clampmentioning

confidence: 99%

Physiological characterization of human muscle acetylcholine receptors from ALS patients

Palma

Inghilleri

Conti

et al. 2011

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

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Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons leading to muscle paralysis. Research in transgenic mice suggests that the muscle actively contributes to the disease onset, but such studies are difficult to pursue in humans and in vitro models would represent a good starting point. In this work we show that tiny amounts of muscle from ALS or from control denervated muscle, obtained by needle biopsy, are amenable to functional characterization by two different technical approaches: "microtransplantation" of muscle membranes into Xenopus oocytes and culture of myogenic satellite cells. Acetylcholine (ACh)-evoked currents and unitary events were characterized in oocytes and multinucleated myotubes. We found that ALS acetylcholine receptors (AChRs) retain their native physiological characteristics, being activated by ACh and nicotine and blocked by α-bungarotoxin (α-BuTX), d-tubocurarine (dTC), and galantamine. The reversal potential of ACh-evoked currents and the unitary channel behavior were also typical of normal muscle AChRs. Interestingly, in oocytes injected with muscle membranes derived from ALS patients, the AChRs showed a significant decrease in ACh affinity, compared with denervated controls. Finally, riluzole, the only drug currently used against ALS, reduced, in a dose-dependent manner, the ACh-evoked currents, indicating that its action remains to be fully characterized. The two methods described here will be important tools for elucidating the role of muscle in ALS pathogenesis and for developing drugs to counter the effects of this disease.voltage-clamp | patch-clamp

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The “Dying-Back” Phenomenon of Motor Neurons in ALS

Cited by 344 publications

References 55 publications

The Effects of Human Wild-Type and Fals Mutant L144P SOD1 on Non-Vascular Smooth Muscle Contractions / EFEKTI HUMANE NORMALNE I FALS MUTIRANE L144P SOD1 NA NEVASKULARNE KONTRAKCIJE GLATKIH MIŠIĆA

The Effects of Human Wild-Type and Fals Mutant L144P SOD1 on Non-Vascular Smooth Muscle Contractions / EFEKTI HUMANE NORMALNE I FALS MUTIRANE L144P SOD1 NA NEVASKULARNE KONTRAKCIJE GLATKIH MIŠIĆA

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

Physiological characterization of human muscle acetylcholine receptors from ALS patients

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