Neurodegeneration in an inherited form of ALS is non-cell-autonomous, with ALS-causing mutant SOD1 damage developed within multiple cell types. Selective inactivation within motor neurons of an ...ubiquitously expressed mutant SOD1 gene has demonstrated that mutant damage within motor neurons is a determinant of disease initiation, whereas mutant synthesis within neighboring astrocytes or microglia accelerates disease progression. We now report the surprising finding that diminished synthesis (by 70%) within Schwann cells of a fully dismutase active ALS-linked mutant (SOD1G³⁷R) significantly accelerates disease progression, accompanied by reduction of insulin-like growth factor 1 (IGF-1) in nerves. Coupled with shorter disease duration in mouse models caused by dismutase inactive versus dismutase active SOD1 mutants, our findings implicate an oxidative cascade during disease progression that is triggered within axon ensheathing Schwann cells and that can be ameliorated by elevated dismutase activity. Thus, therapeutic down-regulation of dismutase active mutant SOD1 in familial forms of ALS should be targeted away from Schwann cells.
Expression of transforming growth factor alpha (TGFalpha), a member of the epidermal growth factor (EGF) family, is a general response of adult murine motoneurons to genetic and experimental lesions, ...TGFalpha appearing as an inducer of astrogliosis in these situations. Here we address the possibility that TGFalpha expression is not specific to pathological situations but may participate to the embryonic development of motoneurons. mRNA of TGFalpha and its receptor, the EGF receptor (EGFR), were detected by ribonuclease protection assay in the ventral part of the cervical spinal cord from embryonic day 12 (E12) until adult ages. Reverse transcription-PCR amplification of their transcripts from immunopurified E15 motoneurons, associated with in situ double-immunohistological assays, identified embryonic motoneurons as cellular sources of the TGFalpha-EGFR couple. In vitro, TGFalpha promoted the survival of immunopurified E15 motoneurons in a dose-dependent manner, with a magnitude similar to BDNF neuroprotective effects at equivalent concentrations. In a transgenic mouse expressing a human TGFalpha transgene under the control of the metallothionein 1 promoter, axotomy of the facial nerve provoked significantly less degeneration in the relevant motor pool of 1-week-old mice than in wild-type animals. No protection was observed in neonates, when the transgene exhibits only weak expression levels in the brainstem. In conclusion, our results point to TGFalpha as a physiologically relevant candidate for a neurotrophic role on developing motoneurons. Its expression by the embryonic motoneurons, which also synthesize its receptor, suggests that this chemokine is endowed with the capability to promote motoneuron survival in an autocrine-paracrine manner.
System x sub(c) super(-) is a cystine/glutamate antiporter that exchanges extracellular cystine for intracellular glutamate. Cystine is intracellularly reduced to cysteine, a building block of GSH. ...As such, system x sub(c) super(-) can regulate the antioxidant capacity of cells. Moreover, in several brain regions, system x sub(c) super(-) is the major source of extracellular glutamate. As such this antiporter is able to fulfill key physiological functions in the CNS, while evidence indicates it also plays a role in certain brain pathologies. Since the transcription of xCT, the specific subunit of system x sub(c) super(-), is enhanced by the presence of reactive oxygen species and inflammatory cytokines, system x sub(c) super(-) could be involved in toxic extracellular glutamate release in neurological disorders that are associated with increased oxidative stress and neuroinflammation. System x sub(c) super(-) has also been reported to contribute to the invasiveness of brain tumors and, as a source of extracellular glutamate, could participate in the induction of peritumoral seizures. Two independent reviews (Pharmacol. Rev. 64, 2012, 780; Antioxid. Redox Signal. 18, 2013, 522), approached from a different perspective, have recently been published on the functions of system x sub(c) super(-) in the CNS. In this review, we highlight novel achievements and insights covering the regulation of system x sub(c) super(-) as well as its involvement in emotional behavior, cognition, addiction, neurological disorders and glioblastomas, acquired in the past few years. System x sub(c) super(-) constitutes an important source of extrasynaptic glutamate in the brain. By modulating the tone of extrasynaptic metabotropic or ionotropic glutamate receptors, it affects excitatory neurotransmission, the threshold for overexcitation and excitotoxicity and, as a consequence, behavior. This review describes the current knowledge of how system x sub(c) super(-) is regulated and involved in physiological as well as pathophysiological brain functioning. System x sub(c) super(-) constitutes an important source of extrasynaptic glutamate in the brain. By modulating the tone of extrasynaptic metabotropic or ionotropic glutamate receptors, it affects excitatory neurotransmission, the threshold for overexcitation and excitotoxicity and, as a consequence, behavior. This review describes the current knowledge of how system x sub(c) super(-) is regulated and involved in physiological as well as pathophysiological brain functioning.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be ...linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).
In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1*G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.
Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ±32 μg/g vs. 0.16 ±0.008 μg/g, p<0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p=0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs untreated mice (178.5 vs. 166.5 days, p=0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.
These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.
Fondation pour la Recherche Medicale, société française de neurochirurgie, fond d’étude et de recherche du corps médical. Investissements d’avenir ANR-10-IAIHU-06, société française de neurochirurgie (SFNC), fond d’étude et de recherche du corps medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French ministry for high education and research (MENR), CarThera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).
Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease characterized by loss of motor neurons. Using mice carrying a deletable ...mutant gene, diminished mutant expression in astrocytes did not affect onset, but delayed microglial activation and sharply slowed later disease progression. These findings demonstrate that mutant astrocytes are viable targets for therapies to slow progression of non-cell-autonomous killing of motor neurons in ALS.
Msj-1 (mouse sperm cell-specific DnaJ first homologue) is a gene specifically expressed in germ cells at haploid stages. The protein
first appears in round spermatids, accumulates in the ...periacrosomal region of elongating spermatids, and is maintained in
spermatozoa. The msj-1 expression pattern is consistent with a role for this DnaJ protein in the spermiogenesis process. In this study, we used
two experimental models, the anuran amphibian Rana esculenta and the wobbler mutant mouse, to explore the role of MSJ-1 during spermatogenesis, with a focus on spermiogenesis. Mice homozygous
for the recessive mutation wobbler ( wr / wr ), a mutation of unknown identity, produce sperm cells characterized by a missing acrosome. In Rana esculenta testis, detection of high levels of MSJ-1 protein coincided with the appearance of postmeiotic germ cells during the annual
sexual cycle. Conversely, elimination of the meiotic and postmeiotic stages, through gonadotropin administration at low temperature,
abolished the MSJ-1 immunoreactive signal. In 20-day-old mice, when postmeiotic germ cells appeared for the first time, MSJ-1
mRNA and protein were observed in +/+ testis but were barely detectable in wr / wr testis. In adult testis, reduced MSJ-1 protein levels were observed in both +/ wr and wr / wr testis, as compared with +/+ controls. Similarly, numbers of spermatids that stained by immunofluorescence for MSJ-1 appeared
to be progressively reduced in adult +/+, +/ wr , and wr / wr mouse testes, respectively. Characterization of the endocrine status of wobbler testis revealed reduced transcript levels
of estrogen receptor α and reduced intratesticular androgen levels. However, androgen treatment did not affect MSJ-1 protein
levels in either frogs or mice. In conclusion, our data in Rana esculenta and the wobbler mouse demonstrate a tight correlation between MSJ-1 protein expression and postmeiotic stages. In particular,
the findings in the wobbler testis suggest a role for this protein in acrosomogenesis.
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