On the occasion of World ALS Day, we confirm our commitment to studying this serious disease.
Our Brain Development and Disease group has been studying ALS for years and recently published two articles that help clarify some of its causes and suggest new therapeutic options.
Scientific Report, 21 May 2025
Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models.
Daniela Maria Rasà1,2, Ilaria Stoppa1, Noémie Bérenger-Currias3, Elena Pasho4, Sorana Ciura4, Edor Kabashi4, Cécile Martinat3 & *Marina Boido1
Amyotrophic lateral sclerosis (ALS) is a multifactorial motor neuron (MN) disease, characterized by several cellular dysfunctions, many of which are shared by different neurodegenerative diseases. Here, we investigated whether a stressful lifestyle might exacerbate the altered mechanisms and affect the disease progression in ALS-predisposed conditions. To model stress in vivo, SOD1G93A mice underwent a chronic unpredicted mild stress protocol. This resulted in a significant impairment in body weight gain and motor performance, in a gender-specific manner. Moreover, the gene expression of Col1a1, Col1a2 and Il6 was strongly dysregulated in motor cortex and/or spinal cord of stressed mice.
To assess the direct impact of stress on MNs, NSC-34 hSOD1G93A cells underwent oxygen and glucose deprivation. Compared to NSC-34 hSOD1WT, mutated MNs exhibited a reduced capacity to cope with stress. By performing gene expression, protein-protein interaction, gene ontology and pathway enrichment analyses, we also revealed the pivotal role of the PI3K/Akt and focal adhesion pathways (triggered by Gsk3b, Il6, Igf1 and/or collagen) in mediating stress response. Similar results were observed in stressed human iPSCs-derived TARDBPG298S MNs.
In conclusion, our results suggest that the PI3K/Akt and focal adhesion pathways play a crucial role in stress response across different ALS-predisposed models: the study paves the way for novel therapeutic targets and highlights the relevance of a healthy lifestyle.
Bioinformatic analysis shows the main mechanisms (and related genes), dysregulated in healthy or ALS-affected motor neurons, in the presence of stress.
1Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Turin, Italy.
2University School for Advanced Studies IUSS Pavia, Pavia, Italy.
3Université Paris-Saclay, Université d’Evry, Inserm, I-Stem, UMR861, 91100 Corbeil-Essonnes, France 4Laboratory of Translational Research for Neurological Disorders, Imagine Institute, INSERM UMR 1163, 75015, Université Paris Cité, Paris, France.
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Journal of Translational Medicine, 9 May 2025
Safety and efficacy evaluation of intracerebroventricular human neural stem cell transplantation in SOD1 mice as a novel approach for ALS
Ivan Lombardi 1,2, Clelia Ferrero 3,4,5†, Edvige Vulcano 2† , Daniela Maria Rasà3,4,5, Maurizio Gelati6, Diego Pastor7, Rose Mary Carletti6, Silvia de la Morena3,4, Daniela Celeste Profico6 , Sabrina Longobardi2, Elisa Lazzarino3,4, Elisa Perciballi2,6, Jessica Diana Rosati8,9, Salvador Martinez10, Alessandro Vercelli3,4, Angelo Luigi Vescovi11,12, Marina Boido3,4* and Daniela Ferrari2*
Background
Neural stem cell (NSC) transplantation holds promising therapeutic potential for neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). However, pre-clinical studies and early-phase clinical trials have faced challenges hindering the effective clinical translation of this approach. Crucial hurdles include the side-effects of prolonged immunosuppression, concerns regarding cell origin and transplantation dosage, identification of the most appropriate therapeutic window, and invasiveness of surgical procedures. Here, we assessed the safety and efficacy of intracerebroventricular (ICV) hNSC transplantation as a novel and possibly more effective experimental approach for ALS.
Methods
We evaluated the safety of administering up to 1 × 106 hNSCs in immunodeficient mice and assessed their potential efficacy in reducing ALS hallmarks employing the SOD1G93A mouse model. Both transient (15 days) and prolonged immunosuppression regimens, at low (15 mg/kg) and high (30 mg/kg) doses, were tested along with two different cell dosages (3 × 105 and 1 × 106).
Results
Our study suggests that: (i) a bilateral ICV transplantation of 1 × 106 hNSCs is safe and non-tumorigenic in immunodeficient hosts; (ii) sustained and high-dose immunosuppression is essential for ensuring cell survival in immunocompetent SOD1G93A mice; and (iii) hNSCs may delay motor symptom progression and reduce spinal cord microgliosis in SOD1G93A mice when administered in the lateral ventricles under prolonged high-dose (30 mg/kg) immunosuppression.
The graft of one million human neural stem cells (NSCs) into the cerebral ventricles of ALS mice, under immunosuppression with cyclosporine, allows for the improvement of motor performance and the reduction of microglia activation (labeled in green with IBA1), also partially affecting the survival of motor neurons.
† Clelia Ferrero and Edvige Vulcano contributed equally to this work.
† Marina Boido and Daniela Ferrari co-last and co-corresponding to
this work
1 School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
2 Department of Biotechnology and Biosciences, University of Milano- Bicocca, Milan, Italy
3 Neuroscience Institute Cavalieri Ottolenghi (N.I.C.O.), University of Turin, Turin, Italy
4 Department of Neuroscience “Rita Levi Montalcini”, University of Turin, Turin, Italy
5 University School for Advanced Studies IUSS Pavia, Pavia, Italy
6 Production Unit of Advanced Therapies (UPTA), Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
7 Sport Research Centre, Miguel Hernández University, Avinguda de la Universitat d’Elx, Elche, Spain
8 Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
9 UniCamillus – Saint Camillus International University of Health Sciences, Rome, Italy