Motor neuron degeneration, severe myopathy and TDP-43 increase in a transgenic pig model of SOD1-linked familiar ALS

Crociara, Paola; Chieppa, MN; Costassa, Elena Vallino; Berrone, Elena; Gallo, Marina; Faro, Mònica; Pintore, Maria Domenica; Iulini, Barbara; D’Angelo, Antonio; Perona, Giovanni Emilio; Botter, Alberto; Formicola, Donato; Rainoldi, Alberto; Paulis, Marianna; Vezzoni, Paolo; Meli, Federica; Peverali, Fiorenzo A.; Bendotti, Caterina; Trolese, Maria Chiara; Pasetto, Laura; Bonetto, Valentina; Lazzari, Giovanna; Duchi, Roberto; Perota, Andrea; Lagutina, Irina; Quadalti, Corinne; Gennero, Maria Silvia; Dezzutto, Daniela; Desiato, Rosanna; Boido, Marina; Ghibaudi, Matilde; Valentini, Maria Consuelo; Caramelli, Maria; Galli, Cesare; Casalone, Cristina

doi:10.1016/j.nbd.2018.11.021

Cited by 19 publications

(14 citation statements)

References 54 publications

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“…The hypothesis that skeletal muscle may be a primary disease target of mutant SOD1-mediated toxicity is supported by several studies in animal models [22][23][24]. A clear myopathy has not been described in any patient with SOD1 mutations.…”

Section: Discussionmentioning

confidence: 99%

SOD1 p.D12Y variant is associated with amyotrophic lateral sclerosis/distal myopathy spectrum

Tasca

Lattante

Marangi

et al. 2020

Euro J of Neurology

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Background and purpose: The aim of our study was to describe patients with the p.D12Y variant (previously reported as D11Y) in SOD1 showing heterogeneous clinicopathological features. Methods: We performed clinical, electrophysiological, magnetic resonance imaging (MRI) and muscle pathology studies in four SOD1 p.D12Y variantpositive patients. Results: The SOD1 p.D12Y clinical manifestations ranged from a benign phenotype characterized by distal distribution of muscular weakness and long survival to classic forms of amyotrophic lateral sclerosis with poor prognosis. Two patients with the distal clinical phenotype showed MRI and muscle pathology alterations indicating a concurrent muscle involvement. In one of these patients significant myopathic changes were associated with rimmed vacuolar pathology. Conclusions: We expand the clinical spectrum of SOD1 p.D12Y variant, including predominant lower motor neuron forms with long survival and classic forms with aggressive course. Some patients may have concomitant distal myopathy without other explanations. Given clinical, MRI and muscle pathology alterations, SOD1 should be considered in the differential diagnosis of molecularly undefined distal myopathies with rimmed vacuoles.

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Section: Discussionmentioning

confidence: 99%

SOD1 p.D12Y variant is associated with amyotrophic lateral sclerosis/distal myopathy spectrum

Tasca

Lattante

Marangi

et al. 2020

Euro J of Neurology

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“…Animal models are widely used in ALS research especially with the goal to investigate underlying mechanisms of disease pathogenesis. Therefore, animal models of the most common ALS pathogenic variants, not only on mice but also on monkeys and pigs, have been created to perform electrophysiological studies [ 139 ] and to test drugs at the pre-symptomatic stage [ 140 ]. All these models are expensive and time-consuming and therefore not applicable to test the pathogenicity of all novel variants.…”

Section: Applying the Acmg Standards And Guidelines For The Interpmentioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

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The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS.

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“…4a, b). To corroborate the beneficial effect of hNSCs, we evaluated the presence of misfolded SOD1 deposits by using the SEDI antibody 30,31 . Of note, in the anterior horns of hNSC animals, at 40DAT, SOD1 deposits appeared reduced respect to both control groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats

et al. 2019

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Stem cells are emerging as a therapeutic option for incurable diseases, such as Amyotrophic Lateral Sclerosis (ALS). However, critical issues are related to their origin as well as to the need to deepen our knowledge of the therapeutic actions exerted by these cells. Here, we investigate the therapeutic potential of clinical-grade human neural stem cells (hNSCs) that have been successfully used in a recently concluded phase I clinical trial for ALS patients (NCT01640067). The hNSCs were transplanted bilaterally into the anterior horns of the lumbar spinal cord (four grafts each, segments L3–L4) of superoxide dismutase 1 G93A transgenic rats (SOD1 rats) at the symptomatic stage. Controls included untreated SOD1 rats (CTRL) and those treated with HBSS (HBSS). Motor symptoms and histological hallmarks of the disease were evaluated at three progressive time points: 15 and 40 days after transplant (DAT), and end stage. Animals were treated by transient immunosuppression (for 15 days, starting at time of transplantation). Under these conditions, hNSCs integrated extensively within the cord, differentiated into neural phenotypes and migrated rostro-caudally, up to 3.77 ± 0.63 cm from the injection site. The transplanted cells delayed decreases in body weight and deterioration of motor performance in the SOD1 rats. At 40DAT, the anterior horns at L3–L4 revealed a higher density of motoneurons and fewer activated astroglial and microglial cells. Accordingly, the overall survival of transplanted rats was significantly enhanced with no rejection of hNSCs observed. We demonstrated that the beneficial effects observed after stem cell transplantation arises from multiple events that counteract several aspects of the disease, a crucial feature for multifactorial diseases, such as ALS. The combination of therapeutic approaches that target different pathogenic mechanisms of the disorder, including pharmacology, molecular therapy and cell transplantation, will increase the chances of a clinically successful therapy for ALS.

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Motor neuron degeneration, severe myopathy and TDP-43 increase in a transgenic pig model of SOD1-linked familiar ALS

Cited by 19 publications

References 54 publications

SOD1 p.D12Y variant is associated with amyotrophic lateral sclerosis/distal myopathy spectrum

SOD1 p.D12Y variant is associated with amyotrophic lateral sclerosis/distal myopathy spectrum

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats

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