A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.
Ufmylation is the post-translational modification of proteins through the addition of UFM1. Nahorksi et al. identify mutations in UFM1 and in UFC1, which encodes an enzyme required for ufmylation, in individuals with severe early-onset encephalopathy with progressive microcephaly. The findings suggest an essential role for ufmylation in human brain development.
Oxford, Headington, Oxford, OX3 9DU, UK 41 42 §) Contributed equally, arranged alphabetically 43 †) Corresponding authors 44 45 46 Summary 47 48 Plasmodium simium, a malaria parasite of non-human primates in the Atlantic forest region of 49Brazil was recently shown to cause zoonotic infection in humans in the region. Phylogenetic 50 analyses based on the whole genome sequences of six P. simium isolates infecting humans 51 and two isolates from brown howler monkeys revealed that P. simium is monophyletic within 52 the broader diversity of South American Plasmodium vivax, consistent with the hypothesis 53 that P. simium first infected non-human primates as a result of a host-switch from humans 54 carrying P. vivax. We provide molecular evidence that the current zoonotic infections of 55 people have likely resulted from multiple independent host switches, each seeded from a 56 different monkey infection. Very low levels of genetic diversity within P. simium genomes 57 and the absence of P. simium-P. vivax hybrids suggest that the P. simium population emerged 58 recently and has subsequently experienced a period of independent evolution in Platyrrhini 59 monkeys. We further find that Plasmodium Interspersed Repeat (PIR) genes, Plasmodium 60Helical Interspersed Subtelomeric (PHIST) genes and Tryptophan-Rich Antigens (TRAg) 61 genes in P. siumium are genetically divergent from P. vivax and are enriched for non-62 synonymous single nucleotide polymorphisms, consistent with the rapid evolution of these 63 genes. Analysis of genes involved in erythrocyte invasion revealed several notable differences 64 between P. vivax and P. simium, including large deletions within the coding region of the 65 Duffy Binding Protein 1 (DBP1) and Reticulocyte Binding Protein 2a (RBP2a) genes in P. 66 simium. Genotyping of P. simium isolates from non-human primates (NHPs) and zoonotic 67 human infections showed that a precise deletion of 38 amino acids in DBP1 is exclusively 67 present in all human infecting isolates, whereas non-human primate infecting isolates were 68 polymorphic for the deletion. We speculate that these deletions in the parasite-encoded key 69 erythrocyte invasion ligands and the additional rapid genetic changes have facilitated zoonotic 70 transfer to humans. Non-human primate malaria parasites can be considered a reservoir of 71 potential infectious human parasites that must be considered in any attempt of malaria 72 elimination. The genome of P. simium will thus form an important basis for future functional 73 characterizations on the mechanisms underlying malaria zoonosis. 74 75 76 Introduction 77 78 There are currently eight species of malaria parasites known to cause disease in humans; 79 Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale 80 curtisi, Plasmodium ovale wallikeri, Plasmodium knowlesi, Plasmodium cynomolgi and 81 Plasmodium simium. The latter three species are more commonly parasitic on non-human 82 primates and have only relatively recently been shown to infect humans 1-3 . ...
Background Plasmodium simium, a malaria parasite of non-human primates (NHP), was recently shown to cause zoonotic infections in humans in Brazil. We sequenced the P. simium genome to investigate its evolutionary history and to identify any genetic adaptions that may underlie the ability of this parasite to switch between host species. Results Phylogenetic analyses based on whole genome sequences of P. simium from humans and NHPs reveals that P. simium is monophyletic within the broader diversity of South American Plasmodium vivax, suggesting P. simium first infected NHPs as a result of a host switch of P. vivax from humans. The P. simium isolates show the closest relationship to Mexican P. vivax isolates. Analysis of erythrocyte invasion genes reveals differences between P. vivax and P. simium, including large deletions in the Duffy-binding protein 1 (DBP1) and reticulocyte-binding protein 2a genes of P. simium. Analysis of P. simium isolated from NHPs and humans revealed a deletion of 38 amino acids in DBP1 present in all human-derived isolates, whereas NHP isolates were multi-allelic. Conclusions Analysis of the P. simium genome confirmed a close phylogenetic relationship between P. simium and P. vivax, and suggests a very recent American origin for P. simium. The presence of the DBP1 deletion in all human-derived isolates tested suggests that this deletion, in combination with other genetic changes in P. simium, may facilitate the invasion of human red blood cells and may explain, at least in part, the basis of the recent zoonotic infections.
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