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Sassone J.,IRCCS Foundation Carlo Besta Neurological Institute | Taiana M.,IRCCS Foundation Carlo Besta Neurological Institute | Lombardi R.,IRCCS Foundation Carlo Besta Neurological Institute | Porretta-Serapiglia C.,IRCCS Foundation Carlo Besta Neurological Institute | And 7 more authors.
Human Molecular Genetics | Year: 2016

Growing evidence suggests that amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease that primarily affects motor neurons and, though less evidently, other neuronal systems. About 75% of sporadic and familial ALS patients show a subclinical degeneration of small-diameter fibers, as measured by loss of intraepidermal nerve fibers (IENFs), but the underlying biological causes are unknown. Small-diameter fibers are derived from small-diameter sensory neurons, located in dorsal root ganglia (DRG), whose biochemical hallmark is the expression of type III intermediate filament peripherin.We tested here the hypothesis that small-diameter DRG neurons of ALS mouse model SOD1G93A suffer fromaxonal stress and investigated the underlying molecular mechanism. We found that SOD1G93A mice display small fiber pathology, as measured by IENF loss, which precedes the onset of the disease. In vitro small-diameter DRG neurons of SOD1G93A mice showaxonal stress features and accumulation of a peripherin splice variant, named peripherin56, which causes axonal stress through disassembling light and medium neurofilament subunits (NFL and NFM, respectively). Our findings first demonstrate that small-diameter DRG neurons of the ALS mouse model SOD1G93A display axonal stress in vitro and in vivo, thus sustaining the hypothesis that the effects of ALS disease spread beyond motor neurons. These results suggest a molecular mechanism for the small fiber pathology found in ALS patients. Finally, our data agree with previous findings, suggesting a key role of peripherin in the ALS pathogenesis, thus highlighting that DRG neurons mirror some dysfunctions found in motor neurons. © The Author 2016. Source


Riva N.,San Raffaele Scientific Institute | Chaabane L.,San Raffaele Scientific Institute | Peviani M.,San Raffaele Scientific Institute | Ungaro D.,San Raffaele Scientific Institute | And 12 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2014

Growing evidence indicates that alterations within the peripheral nervous system (PNS) are involved at an early stage in the amyotrophic lateral sclerosis (ALS) pathogenetic cascade. In this study, magnetic resonance imaging (MRI), neurophysiologic analyses, and histologic analyses were used to monitor the extent of PNS damage in the hSOD-1 ALS rat model. The imaging signature of the disease was defined using in vivo MRI of the sciatic nerve. Initial abnormalities were detected in the nerves by an increase in T2 relaxation time before the onset of clinical disease; diffusion MRI showed a progressive increase in mean and radial diffusivity and reduction of fractional anisotropy at advanced stages of disease. Histologic analysis demonstrated early impairment of the blood-nerve barrier followed by acute axonal degeneration associated with endoneurial edema and macrophage response in motor nerve compartments. Progressive axonal degeneration and motor nerve fiber loss correlated with MRI and neurophysiologic changes. These functional and morphologic investigations of the PNS might be applied in following disease progression in preclinical therapeutic studies. This study establishes the PNS signature in this rat ALS model (shedding new light into pathogenesis) and provides a rationale for translating into future systematic MRI studies of PNS involvement in patients with ALS. Copyright © 2014 by the American Association of Neuropathologists, Inc. Source


Armogida M.,Cervello | Spalloni A.,Laboratory of Molecular Neurobiology | Amantea D.,University of Calabria | Nutini M.,Laboratory of Molecular Neurobiology | And 7 more authors.
International Journal of Immunopathology and Pharmacology | Year: 2011

The present study aims to assess the protective role of the antioxidant enzyme catalase (CAT) with relation to hydrogen peroxide (H 2O 2) degradation in oxygen plus water on electrophysiological and fluorescence changes induced by in vitro ischemia and on brain damage produced by transient in vivo ischemia. Neuroprotective effects of CAT were determined by means of electrophysiological recordings and confocal fluorescence microscopy in the hippocampal slice preparation. Ischemia was simulated in vitro by oxygen/glucose deprivation (OGD). In vivo ischemia was produced by transient middle cerebral artery occlusion (MCAo). A protection of the rat CA1 field excitatory postsynaptic potential (fEPSP) loss caused by a prolonged OGD (40 min) was observed after exogenous CAT (500 U/mL) bath-applied before a combined exposure to OGD and H 2O 2 (3 mM). Of note, neither H 2O 2 nor exogenous CAT alone had a protective action when OGD lasted for 40 min. The CAT-induced neuroprotection was confirmed in a transgenic mouse model over-expressing human CAT [Tg(CAT)]. In the presence of H 2O 2, the hippocampus of Tg(CAT) showed an increased resistance against OGD compared to that of wild-type (WT) animals. Moreover, CAT treatment reduced for about 50 min fEPSP depression evoked by repeated applications of H 2O 2 in normoxia. A lower sensitivity to H 2O 2-induced depression of fEPSPs was also indicated by the rightward shift of concentration-response curve in Tg(CAT) compared to WT mice. Noteworthy, Tg(CAT) mice had a reduced infarct size after MCAo. Our data suggest new strategies to reduce neuronal damage produced by transient brain ischemia through the manipulation of CAT enzyme. Copyright © by BIOLIFE, s.a.s. Source


Caron I.,Laboratory of Molecular Neurobiology | Micotti E.,Laboratory of Biology of Neurodegenerative Disorders | Paladini A.,Laboratory of Biology of Neurodegenerative Disorders | Merlino G.,Laboratory of Molecular Neurobiology | And 4 more authors.
PLoS ONE | Year: 2015

Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal disease due to motoneuron degeneration. Magnetic resonance imaging (MRI) is becoming a promising non-invasive approach to monitor the disease course but a direct correlation with neuropathology is not feasible in human. Therefore in this study we aimed to examine MRI changes in relation to histopathology in two mouse models of ALS (C57BL6/J and 129S2/SvHsd SOD1G93A mice) with different disease onset and progression. A longitudinal in vivo analysis of T2 maps, compared to ex vivo histological changes, was performed on cranial motor nuclei. An increased T2 value was associated with a significant tissue vacuolization that occurred prior to motoneuron loss in the cranial nuclei of C57 SOD1G93A mice. Conversely, in 129Sv SOD1G93A mice, which exhibit a more severe phenotype, MRI detected a milder increase of T2 value, associated with a milder vacuolization. This suggests that alteration within brainstem nuclei is not predictive of a more severe phenotype in the SOD1G93A mouse model. Using an ex vivo paradigm, Diffusion Tensor Imaging was also applied to study white matter spinal cord degeneration. In contrast to degeneration of cranial nuclei, alterations in white matter and axons loss reflected the different disease phenotype of SOD1G93A mice. The correspondence between MRI and histology further highlights the potential of MRI to monitor progressive motoneuron and axonal degeneration non-invasively in vivo. The identification of prognostic markers of the disease nevertheless requires validation in multiple models of ALS to ensure that these are not merely model-specific. Eventually this approach has the potential to lead to the development of robust and validated non-invasive imaging biomarkers in ALS patients, which may help to monitor the efficacy of therapies. © 2015 Caron et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source


Nardo G.,Laboratory of Molecular Neurobiology | Nardo G.,University of Sheffield | Iennaco R.,Laboratory of Molecular Neurobiology | Fusi N.,University of Sheffield | And 7 more authors.
Brain | Year: 2013

Amyotrophic lateral sclerosis is heterogeneous with high variability in the speed of progression even in cases with a defined genetic cause such as superoxide dismutase 1 (SOD1) mutations. We reported that SOD1G93A mice on distinct genetic backgrounds (C57 and 129Sv) show consistent phenotypic differences in speed of disease progression and life-span that are not explained by differences in human SOD1 transgene copy number or the burden of mutant SOD1 protein within the nervous system. We aimed to compare the gene expression profiles of motor neurons from these two SOD1G93A mouse strains to discover the molecular mechanisms contributing to the distinct phenotypes and to identify factors underlying fast and slow disease progression. Lumbar spinal motor neurons from the two SOD1G93A mouse strains were isolated by laser capture microdissection and transcriptome analysis was conducted at four stages of disease. We identified marked differences in the motor neuron transcriptome between the two mice strains at disease onset, with a dramatic reduction of gene expression in the rapidly progressive (129Sv-SOD1 G93A) compared with the slowly progressing mutant SOD1 mice (C57-SOD1G93A) (1276 versus 346; Q-value ≤ 0.01). Gene ontology pathway analysis of the transcriptional profile from 129Sv-SOD1G93A mice showed marked downregulation of specific pathways involved in mitochondrial function, as well as predicted deficiencies in protein degradation and axonal transport mechanisms. In contrast, the transcriptional profile from C57-SOD1G93A mice with the more benign disease course, revealed strong gene enrichment relating to immune system processes compared with 129Sv-SOD1G93A mice. Motor neurons from the more benign mutant strain demonstrated striking complement activation, over-expressing genes normally involved in immune cell function. We validated through immunohistochemistry increased expression of the C3 complement subunit and major histocompatibility complex I within motor neurons. In addition, we demonstrated that motor neurons from the slowly progressing mice activate a series of genes with neuroprotective properties such as angiogenin and the nuclear factor (erythroid-derived 2)-like 2 transcriptional regulator. In contrast, the faster progressing mice show dramatically reduced expression at disease onset of cell pathways involved in neuroprotection. This study highlights a set of key gene and molecular pathway indices of fast or slow disease progression which may prove useful in identifying potential disease modifiers responsible for the heterogeneity of human amyotrophic lateral sclerosis and which may represent valid therapeutic targets for ameliorating the disease course in humans. © The Author (2013). Source

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