Mini-chromosome maintenance complexes form a filament to remodel DNA structure and topology.

Deregulation of mini-chromosome maintenance (MCM) proteins is associated with genomic instability and cancer. MCM complexes are recruited to replication origins for genome duplication. Paradoxically, MCM proteins are in excess than the number of origins and are associated with chromatin regions away from the origins during G1 and S phases. Here, we report an unusually wide left-handed filament structure for an archaeal MCM, as determined by X-ray and electron microscopy. The crystal structure reveals that an α-helix bundle formed between two neighboring subunits plays a critical role in filament formation. The filament has a remarkably strong electro-positive surface spiraling along the inner filament channel for DNA binding. We show that this MCM filament binding to DNA causes dramatic DNA topology change. This newly identified function of MCM to change DNA topology may imply a wider functional role for MCM in DNA metabolisms beyond helicase function. Finally, using yeast genetics, we show that the inter-subunit interactions, important for MCM filament formation, play a role for cell growth and survival

Discovery and Characterization of Iron Sulfide and Polyphosphate Bodies Coexisting in Archaeoglobus fulgidus

Inorganic storage granules have long been recognized in bacterial and eukaryotic cells but were only recently identified in archaeal cells. Here, we report the cellular organization and chemical compositions of storage granules in the Euryarchaeon, Archaeoglobus fulgidus strain VC16, a hyperthermophilic, anaerobic, and sulfate-reducing microorganism. Dense granules were apparent in A. fulgidus cells imaged by cryo electron microscopy (cryoEM) but not so by negative stain electron microscopy. Cryo electron tomography (cryoET) revealed that each cell contains one to several dense granules located near the cell membrane. Energy dispersive X-ray (EDX) spectroscopy and scanning transmission electron microscopy (STEM) show that, surprisingly, each cell contains not just one but often two types of granules with different elemental compositions. One type, named iron sulfide body (ISB), is composed mainly of the elements iron and sulfur plus copper; and the other one, called polyphosphate body (PPB), is composed of phosphorus and oxygen plus magnesium, calcium, and aluminum. PPBs are likely used for energy storage and/or metal sequestration/detoxification. ISBs could result from the reduction of sulfate to sulfide via anaerobic energy harvesting pathways and may be associated with energy and/or metal storage or detoxification. The exceptional ability of these archaeal cells to sequester different elements may have novel bioengineering applications

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Structural Analysis of Cell Components and Cell division in Archaeal Cells

Archaea occupy one of the three domains of life and it is recognized that many of their cellular processes bear more similarity to their analogous processes in eukaryotic cells than the comparable processes in prokaryotic cells. However, despite the fact that archaeal cells are similar in complexity to bacterial cells, they have been studied to a much lesser extent, with the majority of species yet to be examined at all in the laboratory. Further study of this domain of life can be expected to contribute to the understanding of the cellular processes in higher organisms, including humans. In particular, very little is known about the structures and morphogenesis of archaeal cells. The studies described here aim to fill this knowledge gap by examining and resolving the structures of archaeal cells under a variety of conditions and with different techniques. Specifically, this work characterized the unique structural components of archaeal cells, analyzed the properties of concentrated inclusion bodies, and examined structural changes throughout cell division in archaeal cells. A combination of biophysical methods, including cryo electron microscopy (cryo EM), cryo electron tomography (cryo ET), scanning transmission EM (STEM) tomography, and energy dispersive x-ray (EDX) spectroscopy, were used to identify and characterize high-density polyphosphate bodies distributed within the Methanospirillum hungatei cell cytoplasm, two distinct high-density inclusion bodies distributed within the Archeaoglobus fulgidus cytoplasm, and the processes of cell division in both M. hungatei and A. fulgidus

Structural Analysis of Cell Components and Cell division in Archaeal Cells

Archaea occupy one of the three domains of life and it is recognized that many of their cellular processes bear more similarity to their analogous processes in eukaryotic cells than the comparable processes in prokaryotic cells. However, despite the fact that archaeal cells are similar in complexity to bacterial cells, they have been studied to a much lesser extent, with the majority of species yet to be examined at all in the laboratory. Further study of this domain of life can be expected to contribute to the understanding of the cellular processes in higher organisms, including humans. In particular, very little is known about the structures and morphogenesis of archaeal cells. The studies described here aim to fill this knowledge gap by examining and resolving the structures of archaeal cells under a variety of conditions and with different techniques. Specifically, this work characterized the unique structural components of archaeal cells, analyzed the properties of concentrated inclusion bodies, and examined structural changes throughout cell division in archaeal cells. A combination of biophysical methods, including cryo electron microscopy (cryo EM), cryo electron tomography (cryo ET), scanning transmission EM (STEM) tomography, and energy dispersive x-ray (EDX) spectroscopy, were used to identify and characterize high-density polyphosphate bodies distributed within the Methanospirillum hungatei cell cytoplasm, two distinct high-density inclusion bodies distributed within the Archeaoglobus fulgidus cytoplasm, and the processes of cell division in both M. hungatei and A. fulgidus