*7.1. M Protein*

In SSPE, uridine-to-cytidine biased hypermutations of M protein are characteristic [107]. Studies have shown that MeV can evade the innate immunity control by taking advantage of the adenosine deaminase acting on RNA 1 (ADAR1), an IFN-stimulated gene that binds double-stranded RNA and converts adenosine to inosine by deamination [108]. The biased hypermutations in M (and other) gene in SSPE (or MIBE) cases might also be related to ADAR1 activity. Hypermutation of M protein leads to an unstable and defective M protein in viral particles assembly [109]. As a result, the virus is defective in budding from the plasma membranes and cannot produce viral particles. Among the large number of mutations in mRNA, the lack of the AUG initiation codon is leading to a low expression of M protein [110]. Nevertheless, in the context of brain invasion, the hypermutated M gene still allows MeV to replicate, spread, and cause disease [111,112]. Indeed, M protein negatively regulates the viral polymerase activity and thus to impact mRNA transcription and genome replication [113]. One of the roles of M protein is the distribution of both F and H glycoproteins at the apical cell surface [114]. Thereby, mutations in M protein could impact the virus fusion (and F stabilization), through association with surface glycoproteins tails, and thus influence the virus dissemination through the brain. Although in transgenic mice the infection with a M hypermutated MeV induces a more fusogenic phenotype despite attenuated budding, resulting in a more suitable virus for brain infection [111]. Other mutations impact interactions with the viral nucleocapsid and surface glycoproteins [115,116]. This provides

another explanation for the absence of viral particle productions in SSPE-patient brains. This lack of budding is a key property highlighting that patients are non-contagious [93]. While numerous studies report the isolation of SSPE infectious viral particles from patient brains, none of them have physically shown whether classic infectious viral particles or virus RNP-containing apoptotic bodies expressing surface glycoproteins were effectively isolated [107,117–120].
