Backstrom, D. | bioRxiv Science

bioRxiv2024

Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson's disease and Dementia with Lewy bodies

GBA is the major risk gene for Parkinsons disease (PD) and Dementia with Lewy Bodies (DLB), two common -synucleinopathies with cognitive deficits. We investigated the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice showed early cognitive deficits but lacked PD-like motor deficits or -synuclein pathology. Conversely, SNCA tg mice displayed age-related motor deficits, without cognitive abnormalities. Gba-SNCA mice exhibited both cognitive decline and exacerbated motor deficits, accompanied by greater cortical phospho--synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via robust downregulation of genes regulating SV cycle and synapse assembly. Immunohistochemistry and electron microscopy validated these findings. Our results indicate that Gba mutations, while exacerbating pre-existing -synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through -synuclein-independent mechanisms, involving dysfunction in SV endocytosis.

neuroscience↗

bioRxiv2018

Virus genomes from deep sea sediments expand the ocean megavirome and support independent origins of viral gigantism

The Nucleocytoplasmic Large DNA Viruses (NCLDV) of eukaryotes (proposed order \"Megavirales\") include the families Poxviridae, Asfarviridae, Iridoviridae, Ascoviridae, Phycodnaviridae, Marseilleviridae, and Mimiviridae, as well as still unclassified Pithoviruses, Pandoraviruses, Molliviruses and Faustoviruses. Several of these virus groups include giant viruses, with genome and particle sizes exceeding those of many bacterial and archaeal cells. We explored the diversity of the NCLDV in deep-sea sediments from the Lokis Castle hydrothermal vent area. Using metagenomics, we reconstructed 23 high quality genomic bins of novel NCLDV, 15 of which are closest related to Pithoviruses, 5 to Marseilleviruses, 1 to Iridoviruses, and 2 to Klosneuviruses. Some of the identified Pitho-like and Marseille-like genomes belong to deep branches in the phylogenetic tree of core NCLDV genes, substantially expanding the diversity and phylogenetic depth of the respective groups. The discovered viruses have a broad range of apparent genome sizes including putative giant members of the family Marseilleviridae, in agreement with multiple, independent origins of gigantism in different branches of the NCLDV. Phylogenomic analysis reaffirms the monophyly of the Pitho-Irido-Marseille branch of NCLDV. Similarly to other giant viruses, the Pitho-like viruses from Lokis Castle encode translation systems components. Phylogenetic analysis of these genes indicates a greater bacterial contribution than detected previously. Genome comparison suggests extensive gene exchange between members of the Pitho-like viruses and Mimiviridae. Further exploration of the genomic diversity of \"Megavirales\" in additional sediment samples is expected to yield new insights into the evolution of giant viruses and the composition of the ocean megavirome.\n\nImportanceGenomics and evolution of giant viruses is one of the most vigorously developing areas of virus research. Lately, metagenomics has become the main source of new virus genomes. Here we describe a metagenomic analysis of the genomes of large and giant viruses from deep sea sediments. The assembled new virus genomes substantially expand the known diveristy of the Nucleo-Cytoplasmic Large DNA Viruses of eukaryotes. The results support the concept of independent evolution of giant viruses from smaller ancestors in different virus branches.

microbiology↗