| 1. |
- Arstikaitis, Pamela, et al.
(författare)
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Paralemmin-1, a modulator of filopodia induction is required for spine maturation
- 2008
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Ingår i: Molecular Biology of the Cell. - : ASCB. - 1059-1524 .- 1939-4586. ; 19:5, s. 2026-2038
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic filopodia are thought to participate in neuronal contact formation and development of dendritic spines, however, molecules that regulate filopodia extension and their maturation to spines remain largely unknown. Here we identify paralemmin-1 as a regulator of filopodia induction and spine maturation. Paralemmin-1 localizes to dendritic membranes, and its ability to induce filopodia and recruit synaptic elements to contact sites requires protein acylation. Effects of paralemmin-1 on synapse maturation are modulated by alternative splicing that regulates spine formation and recruitment of AMPA-type glutamate receptors. Paralemmin-1 enrichment at the plasma membrane is subject to rapid changes in neuronal excitability, and this process controls neuronal activity-driven effects on protrusion expansion. Knockdown of paralemmin-1 in developing neurons reduces the number of filopodia and spines formed and diminishes the effects of Shank1b on the transformation of existing filopodia into spines. Our study identifies a key role for paralemmin-1 in spine maturation through modulation of filopodia induction.
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| 2. |
- Ballantyne, Kaye N., et al.
(författare)
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Toward Male Individualization with Rapidly Mutating Y-Chromosomal Short Tandem Repeats
- 2014
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 35:8, s. 1021-1032
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Tidskriftsartikel (refereegranskat)abstract
- Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, greater than99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836-0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father-son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RMY-STRs in identifying and separating unrelated and related males and provides a reference database.
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| 3. |
- Chen, Wei-Ting, et al.
(författare)
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Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease
- 2020
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 182:4, s. 976-
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Tidskriftsartikel (refereegranskat)abstract
- Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer's disease (AD), little is known about the molecular changes and cellular interactions that characterize this response, We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-mu m diameter around amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIGs), whereas a multicellular gene co-expression network of plaque-induced genes (PIGs) involving the complement system, oxidative stress, lysosomes, and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.
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| 4. |
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| 5. |
- McCarthy, Shane, et al.
(författare)
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A reference panel of 64,976 haplotypes for genotype imputation
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1279-1283
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Tidskriftsartikel (refereegranskat)abstract
- We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
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| 6. |
- Sala, Benedetta Maria, et al.
(författare)
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Conformational Stability and Dynamics in Crystals Recapitulate Protein Behavior in Solution
- 2020
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Ingår i: Biophysical Journal. - : Ceii Press. - 0006-3495 .- 1542-0086. ; 119:5, s. 978-988
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Tidskriftsartikel (refereegranskat)abstract
- A growing body of evidences has established that in many cases proteins may preserve most of their function and flexibility in a crystalline environment, and several techniques are today capable to characterize molecular properties of proteins in tightly packed lattices. Intriguingly, in the case of amyloidogenic precursors, the presence of transiently populated states (hidden to conventional crystallographic studies) can be correlated to the pathological fate of the native fold; the low fold stability of the native state is a hallmark of aggregation propensity. It remains unclear, however, to which extent biophysical properties of proteins such as the presence of transient conformations or protein stability characterized in crystallo reflect the protein behavior that is more commonly studied in solution. Here, we address this question by investigating some biophysical properties of a prototypical amyloidogenic system, beta 2-microglobulin in solution and in microcrystalline state. By combining NMR chemical shifts with molecular dynamics simulations, we confirmed that conformational dynamics of beta 2-microglobulin native state in the crystal lattice is in keeping with what observed in solution. A comparative study of protein stability in solution and in crystallo is then carried out, monitoring the change in protein secondary structure at increasing temperature by Fourier transform infrared spectroscopy. The increased structural order of the crystalline state contributes to provide better resolved spectral components compared to those collected in solution and crucially, the crystalline samples display thermal stabilities in good agreement with the trend observed in solution. Overall, this workshows that protein stability and occurrence of pathological hidden states in crystals parallel their solution counterpart, confirming the interest of crystals as a platform for the biophysical characterization of processes such as unfolding and aggregation.
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| 7. |
- Sala Frigerio, Carlo, et al.
(författare)
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Reduced expression of hsa-miR-27a-3p in CSF of patients with Alzheimer disease.
- 2013
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 81:24, s. 2103-2106
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated microRNAs (miRNAs) as potential biomarkers for Alzheimer disease (AD) by analyzing the expression level of miRNAs in CSF of patients with AD dementia and nonaffected control subjects.
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| 8. |
- Szczepankiewicz, Olga, et al.
(författare)
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N-Terminal Extensions Retard Aβ42 Fibril Formation but Allow Cross-Seeding and Coaggregation with Aβ42.
- 2015
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 137:46, s. 14673-14685
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid β-protein (Aβ) sequence length variants with varying aggregation propensity coexist in vivo, where coaggregation and cross-catalysis phenomena may affect the aggregation process. Until recently, naturally occurring amyloid β-protein (Aβ) variants were believed to begin at or after the canonical β-secretase cleavage site within the amyloid β-protein precursor. However, N-terminally extended forms of Aβ (NTE-Aβ) were recently discovered and may contribute to Alzheimer's disease. Here, we have used thioflavin T fluorescence to study the aggregation kinetics of Aβ42 variants with N-terminal extensions of 5-40 residues, and transmission electron microscopy to analyze the end states. We find that all variants form amyloid fibrils of similar morphology as Aβ42, but the half-time of aggregation (t1/2) increases exponentially with extension length. Monte Carlo simulations of model peptides suggest that the retardation is due to an underlying general physicochemical effect involving reduced frequency of productive molecular encounters. Indeed, global kinetic analyses reveal that NTE-Aβ42s form fibrils via the same mechanism as Aβ42, but all microscopic rate constants (primary and secondary nucleation, elongation) are reduced for the N-terminally extended variants. Still, Aβ42 and NTE-Aβ42 coaggregate to form mixed fibrils and fibrils of either Aβ42 or NTE-Aβ42 catalyze aggregation of all monomers. NTE-Aβ42 monomers display reduced aggregation rate with all kinds of seeds implying that extended termini interfere with the ability of monomers to nucleate or elongate. Cross-seeding or coaggregation may therefore represent an important contribution in the in vivo formation of assemblies believed to be important in disease.
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| 9. |
- Visentin, Cristina, et al.
(författare)
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Glycosylation Tunes Neuroserpin Physiological and Pathological Properties
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:9
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Tidskriftsartikel (refereegranskat)abstract
- Neuroserpin (NS) is a member of the serine protease inhibitors superfamily. Specific point mutations are responsible for its accumulation in the endoplasmic reticulum of neurons that leads to a pathological condition named familial encephalopathy with neuroserpin inclusion bodies (FENIB). Wild-type NS presents two N-glycosylation chains and does not form polymers in vivo, while non-glycosylated NS causes aberrant polymer accumulation in cell models. To date, all in vitro studies have been conducted on bacterially expressed NS, de facto neglecting the role of glycosylation in the biochemical properties of NS. Here, we report the expression and purification of human glycosylated NS (gNS) using a novel eukaryotic expression system, LEXSY. Our results confirm the correct N-glycosylation of wild-type gNS. The fold and stability of gNS are not altered compared to bacterially expressed NS, as demonstrated by the circular dichroism and intrinsic tryptophan fluorescence assays. Intriguingly, gNS displays a remarkably reduced polymerisation propensity compared to non-glycosylated NS, in keeping with what was previously observed for wild-type NS in vivo and in cell models. Thus, our results support the relevance of gNS as a new in vitro tool to study the molecular bases of FENIB.
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| 10. |
- Walgrave, Hannah, et al.
(författare)
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Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer's disease.
- 2021
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Ingår i: Cell stem cell. - : Elsevier BV. - 1875-9777 .- 1934-5909. ; 28:10
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Tidskriftsartikel (refereegranskat)abstract
- Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer's disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly affected by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration.
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