Background: The mechanism by which astrocytes contribute to disease progression in mutant SOD1 mouse models of ALS is not known.Results: Mutant SOD1 astrocytes release mutant SOD1-containing exosomes that are toxic for motor neurons.Conclusion: Astrocyte-derived exosomes may have a role in disease spreading and motor neuron pathology.Significance: New therapeutic approaches should target exosomes to contain disease progression.

Changes in the homeostasis of tumor necrosis factor a (TNFa) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFa to the development of ALS is still debated. TNFa is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFa and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1-G93A co-cultures. Deleting TNFR2 from SOD1-G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1-G93A/TNFR2À/À mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane-bound TNFa as Abbreviations used: ALS, amyotrophic lateral sclerosis; Ara-C, arabinoside; BDNF, brain-derived neurotrophic factor; ChAT, choline acetyl transferase; CSF, cerebrospinal fluid; DIV, days in vitro; GFAP, glial fibrillary acidic protein; HBSS, Hank's balanced salt solution; IFNc, interferon c; IL-1b, interleukin 1b; IL-6, interleukin 6; iNOS, inducible NO synthase; LPS, lipopolysaccharides; mTNFa, membrane TNFa; NGS, normal goat serum; NMJ, neuromuscular junctions; PBS, phosphate-buffered saline; PFA, paraformaldehyde; qPCR, quantitative polymerase chain reaction; SDS, sodium dodecyl sulphate; SOD1, superoxide dismutase 1; sTNFa, soluble TNFa; sTNFR2, soluble TNFR2; TBS, tris-buffered solution; TBS-T, tris-buffered solution with Tween; TDP-43, TAR DNA-binding protein 43; Teff, T effector cells; TNFa, tumor necrosis factor a; TNFR1, tumor necrosis factor receptor 1; TNFR2, tumor necrosis factor receptor 2; Treg, regulatory T cells. an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology.

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Un rapido accesso ai nuovi trattamenti efficaci rimane una priorità dell'Agenzia Italiana del Farmaco (AIFA) e del Servizio Sanitario Nazionale (SSN) e un importante traguardo per le aziende farmaceutiche. 1 Poiché molti dei nuovi farmaci sono approvati a livello centralizzato dalla European Medicines Agency (EMA), l'accesso ai nuovi trattamenti riveste anche un carattere di equità comunitario. Proprio per questo, la Legge 189/2012 ha istituito la classe C NN , in cui è previsto che i farmaci approvati con procedura centralizzata sono automaticamente classificati entro 60 giorni dall'ottenimento dell'AIC europea. 2 Questo ne consente la commercializzazione, nonostante non abbiano concluso la procedura negoziale con AIFA (" NN " sta per