Spinal Cord mRNA Profile in Patients with ALS: Comparison with Transgenic Mice Expressing the Human SOD-1 Mutant

Offen, Daniel; Barhum, Yael; Melamed, Eldad; Embacher, Norbert; Schindler, Christoph; Ransmayr, Gerhard

doi:10.1007/s12031-007-9004-z

Cited by 81 publications

(67 citation statements)

References 54 publications

(60 reference statements)

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“…Extensive literature describes the consequences of ALSrelated SOD1 mutations for motor neuron function, inflammatory events as well as gene expression profiles in experimental animal models Offen et al 2009;Wijesekera and Leigh 2009). Accordingly, in our study, a number of transcriptional changes occurring in the LSC of G93A mice are consistent with severe neuronal and/ or glial alterations.…”

Section: Discussionsupporting

confidence: 61%

Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

D’Arrigo¹,

Colavito²,

Peña-Altamira

et al. 2010

J Mol Neurosci

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Mice bearing mutations of copper-zinc-superoxide dismutase recapitulate spinal cord motor neuron degeneration and disease progression occurring in human amyotrophic lateral sclerosis. We have investigated the relationship between disease progression and altered gene expression by comparing the transcriptional profiles in lumbar spinal cord, fronto-parietal cortex and hippocampus of mutant G93A-SOD1, wild-type SOD1 transgenic and non-transgenic mice. Gene expression was evaluated at 55 and 110 days of age, representing pre-symptomatic and advanced disease stages of G93A mice, respectively. Whereas no significant variations were detectable in cortical and hippocampal areas, several mutation-related changes were detected in the lumbar spinal cord at the symptomatic stage, consistent with a condition of neuronal distress. Also, at both ages, we found a number of transgene-related changes, i.e. variations occurring in both transgenic groups independently of the G93A mutation, with wild-type SOD1- and G93A-SOD1-overexpressing mice displaying global transcriptional similarity at 110 days of age. Some of the changes in common between the two transgenic groups involve genes implicated in oxidative stress, inflammation, spinocerebellar degeneration and other neurodegenerative disorders. The finding that gene expressional alterations potentially associated to cellular distress are shared by wild-type and mutant human SOD1-overexpressing mice raises the possibility that mutated (in familial ALS) or otherwise dysregulated (in sporadic ALS) SOD1 expression is a common pathogenetic substrate of the disease.

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Section: Discussionsupporting

confidence: 61%

Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

D’Arrigo¹,

Colavito²,

Peña-Altamira

et al. 2010

J Mol Neurosci

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“…The death of the upper motor neurons, found in the motor cortex in the brain, leads to spasticity, hyperexcitability of reflexes and the appearance of pathological reflexes, such as the Babinski sign. The death of the lower motor neurons, which are found in the brain stem and in the spinal cord, leads to weakness and atrophy of the muscles followed by progressive paralysis (Mohajeri et al 1999;Acsadi et al 2002;Bruijn et al 2004;Séverine et al 2006;Aguilar et al 2007;Lev et al 2009;Offen et al 2009). …”

Section: Introductionmentioning

confidence: 99%

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

2010

Self Cite

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Amyotrophic lateral sclerosis (ALS) is a lethal disease, characterized by progressive death of motor neurons with unknown etiology. Evidence from animal models indicates that neuronal dysfunction precedes the clinical phase of the disease. However, in parallel extensive nerve sprouting and synaptic remodeling as part of a compensatory reinnervation processes and possibly also of motor neurons pathology was demonstrated. Therefore, the weakness in muscle groups will not be clinically apparent until a large proportion of motor units are lost. This motor unit loss and associated muscle function which precedes the death of motor neurons may resemble the "die-back" phenomena. Studies indicated that in the early stages the nerve terminals and motor neuron junctions are partially degraded while the cell bodies in the spinal cord are mostly intact. Treatments to rescue motor neurons according to "dying-forward" model of motor neuron pathology in ALS have shown only limited success in SOD1(G93A) transgenic mice as well as in humans. If cell body degeneration is late compared with axonal degeneration, early intervention could potentially prevent loss of motor neurons. Therefore, it should be considered, according to the dying back hypothesis, to focus on motor neurons terminals in order to delay or prevent the progressive degradation.

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“…In vitro studies have demonstrated that the cell-conditioned medium protected neurons against various neurotoxins. Moreover, in animal models of Parkinson's disease, multiple sclerosis and Huntington's disease, the transplanted cells showed marked improvements [26,27].…”

Section: Introductionmentioning

confidence: 99%

Differentiated Mesenchymal Stem Cells for Sciatic Nerve Injury

Dadon-Nachum

Sadan

Srugo

et al. 2011

Stem Cell Rev and Rep

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Sciatic nerve injury is common and may cause neurological deficits. Previous studies showed that administration of neurotrophic factors (NTFs), naturally occurring proteins that support the development and survival of neurons, preserved and protected damaged motor neuron in the injured sciatic nerve. We have been successful in converting bone marrow-derived mesenchymal stem cells into astrocyte-like cells that produce and secrete NTFs (NTF(+) cells). These cells demonstrate typical astrocyte morphology, express characteristic astrocyte markers and secrete high levels of NTFs. We have already shown that these cells and their conditioned media can protect neurons in culture and in animal models of neurodegenerative diseases. In the current study we examined whether NTF(+) cells are capable of rescuing motor neurons in a rat sciatic nerve injury model, where the right hind limb sciatic nerve was crushed. Rats were transplanted with NTF(+) cells, MSCs or PBS into the lesion site. In rats injected with the NTF(+) cells motor function was markedly preserved. Moreover, NTF(+) cells significantly inhibited the degeneration of the neuromuscular junctions and preserved the myelinated motor axons. Our findings suggest that autologous therapeutic approach can alleviate signs of sciatic nerve injury and probably other neurological disorders.

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Spinal Cord mRNA Profile in Patients with ALS: Comparison with Transgenic Mice Expressing the Human SOD-1 Mutant

Cited by 81 publications

References 54 publications

Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

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

Differentiated Mesenchymal Stem Cells for Sciatic Nerve Injury

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