Abstract - 2018 - Research and Practice in Thrombosis and Haemostasis
Unique Brain Plaques Linked To Alzheimer's Mutation Decoded
Summary: Researchers have identified the structure of amyloid beta fibrils linked to a rare inherited form of Alzheimer's disease caused by the Arctic mutation. Using cryo-electron microscopy and NMR, they revealed a W-shaped fibril structure that explains the formation of cottonwool plaques—large, spherical brain structures unique to this mutation.
These findings enhance our understanding of Alzheimer's mechanisms and could guide the development of targeted therapies. This structural analysis offers hope for treating specific subtypes of Alzheimer's and advancing antibody-based treatments.
Key Facts:
Source: RIKEN
An international collaboration led by RIKEN researchers has discovered how unusual spherical structures form in the brains of people with a mutation that causes a form of inherited Alzheimer's disease.
This discovery could help better understand the mechanics of the debilitating neurodegenerative disease.
Such amyloid beta fibrils are one of the hallmarks of all forms of Alzheimer's disease, although their structures vary according to the disease variety. Credit: Neuroscience NewsWhy Alzheimer's disease strikes some people but not others is still largely mysterious. But in about one percent of cases that reason is clear—the person has inherited one of a handful of mutations that cause familial Alzheimer's.
"The inherited form of Alzheimer's disease can be caused by mutations to the gene that encodes for the amyloid precursor protein," explains Yoshitaka Ishii of the RIKEN Center for Biosystems Dynamics Research.
Some of these mutations promote misfolding of the amyloid beta peptides into fibrillar aggregates, which are amyloid beta molecules clumped together in strings. Such amyloid beta fibrils are one of the hallmarks of all forms of Alzheimer's disease, although their structures vary according to the disease variety.
Discovering the structures of amyloid fibrils of amyloid-beta peptides could shed light on how the disease develops. It could help with developing ways to prevent or treat the condition.
"Amyloid fibrils are key drug targets for antibody therapies for Alzheimer's," says Ishii. "It's thus important to determine their structures."
Now, Ishii and co-workers have prepared samples of amyloid beta fibrils produced by the Arctic mutation—so called because it was first found in Scandinavia. They then used cryo-electron microscopy and solid-state nuclear magnetic resonance (NMR) to determine its structure.
"While Alzheimer's patients with the Arctic mutation exhibit similar symptoms as people with regular Alzheimer's, the pathological features are unique," says Ishii. "For example, a distinctive type of amyloid plaque called cottonwool plaque is often observed."
Cottonwool plaques are large, spherical plaques. "In Alzheimer's patients with the Arctic mutation, cottonwool plaques can be 200 micrometers in diameter, which is ten times larger than a typical plaque," explains Ishii.
"But no one knew how these unique features were produced."
Ishii's team's structural analysis has now revealed how cottonwool plaques may be formed by the mutation. "We've demonstrated that the unique W-shaped structure of amyloid fibrils produced by the Arctic mutation reproduces the major features of cottonwool plaques," says Ishii.
Ishii and his team hope this kind of structural analysis will help Alzheimer's research on two fronts.
"We believe that experimentally creating amyloid fibrils, which mimic the fibrils in various subtypes of Alzheimer's disease, will reveal the complex mechanisms of Alzheimer's," says Ishii.
"This direction should also provide good potential targets for antibody or other therapies for the disorder."
Author: Yoshitaka IshiiSource: RIKENContact: Yoshitaka Ishii – RIKENImage: The image is credited to Neuroscience News
Original Research: Open access."E22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer's" by Yoshitaka Ishii et al. Nature Communications
Abstract
E22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer's
Arctic (E22G) mutation in amyloid-β (Aβ enhances Aβ40 fibril accumulation in Alzheimer's disease (AD). Unlike sporadic AD, familial AD (FAD) patients with the mutation exhibit more Aβ40 in the plaque core. However, structural details of E22G Aβ40 fibrils remain elusive, hindering therapeutic progress.
Here, we determine a distinctive W-shaped parallel β-sheet structure through co-analysis by cryo-electron microscopy (cryoEM) and solid-state nuclear magnetic resonance (SSNMR) of in-vitro-prepared E22G Aβ40 fibrils.
The E22G Aβ40 fibrils displays typical amyloid features in cotton-wool plaques in the FAD, such as low thioflavin-T fluorescence and a less compact unbundled morphology.
Furthermore, kinetic and MD studies reveal previously unidentified in-vitro evidence that E22G Aβ40, rather than Aβ42, may trigger Aβ misfolding in the FAD, and prompt subsequent misfolding of wild-type (WT) Aβ40/Aβ42 via cross-seeding.
The results provide insight into how the Arctic mutation promotes AD via Aβ40 accumulation and cross-propagation.
Cases Of Neurodevelopmental Disorders Caused By Mutated LncRNA CHASERR
1. Three unrelated children were found to have a de novo deletion in the long non-coding RNA (lncRNA) CHASERR, which is adjacent to the chromodomain helicase DNA-binding protein 2 (CHD2), resulting in a syndromic, early-onset neurodevelopmental disorder (NDD).
2. The disease phenotype was distinct from that of patients affected by CHD2 loss-of-function mutations and patient-derived cell lines were found to have increased CHD2 protein levels.
Evidence Rating Level: 4 (Below Average)
Study Rundown: Developmental and epileptic encephalopathies are heterogeneous disorders leading to neurodevelopmental delay. CHD2 is a protein that plays key roles in the neurogenesis of cortical neurons and interneurons, de novo haploinsufficient loss-of-function mutations which lead to phenotypical disorders encompassing seizures, developmental delay, and intellectual disability with normal brain imaging. However, increased CHD2 dosage has not been demonstrated in human disease. CHASERR is a highly conserved lncRNA upstream from CHD2 that represses CHD2 expression, which is essential to postnatal survival in mice, yet its role in human disease remains unclear. This study reported on three unrelated children with a syndromic, early-onset NDD who had a heterozygous de novo deletion within the CHASERR locus. These children shared a phenotype of severe encephalopathy, facial dysmorphisms, cortical atrophy, and cerebral hypomyelination, distinct from that of CHD2 haploinsufficiency. In two of these children, their derived cell lines were found to have increased CHD2 mRNA and CHD2 protein expression, correlated with the loss of CHASERR-mediated repression. These results suggest that CHD2 has a bidirectional dosage sensitivity in human disease and prompt further investigations into other lncRNA-encoding genes.
Click here to read the study in NEJM
In-Depth [case series]: Patient 1 was enrolled in the Undiagnosed Diseases Network and the Rare Genomes Project in the United States. Patients 2 and 3 were enrolled as part of the Génétique Médicale research project in France. The MatchMaker Exchange network connected Patients 1 and 2. Genome sequencing was performed on DNA from peripheral blood samples of the patients and their biological parents. RNA sequencing was performed on blood samples and cultured fibroblasts from Patients 1 and 2. Subsequently, RNA sequencing and quantification of CHD2 protein were conducted on induced pluripotent stem cells from Patients 1 and 2. These children were born after uncomplicated pregnancies and normal growth parameters at birth. Their head circumference percentile decreased at 2 years of age. They shared facial dysmorphic features including widely spaced eyes, anteverted nares, low-set ears, and long philtrum. Developmental delay was noted by two months of age and all three had global delay, and could not verbally communicate, ambulate independently, or perform fine-motor tasks. Encephalopathy was also noted early and by 4 years of age, electroencephalography demonstrated generalized background slowing, with no epileptiform activities noted. Magnetic resonance imaging found cortical atrophy, optic nerve atrophy, cerebral hypomyelination, and thin corpus callosum in all three patients by four years of age. Heterozygous de novo deletions of 22-kb, 8.4-kb, and 25-kb were identified in Patients 1, 2, and 3, encompassing the promoter and exons of CHASERR but not CHD2 or its promoter. In Patients 1 and 2, the de novo deletion occurred on the paternally inherited chromosome, whereas the parental origin of the deletion in Patient 3 could not be determined. Patient 1 demonstrated haploinsufficiency of CHASERR when compared to an unaffected sibling. CHD2 protein level was increased in induced pluripotent stem cells from Patients 1 and 2 by a factor of 1.8 and 1.7. The results suggested that CHD2 has a bidirectional dosage sensitivity in human disease and highlighted the potential role of other lncRNAs in human diseases.
Image: PD
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An Unappreciated Cause Of Disease - Proteins In The Wrong Place
In cells, there is a careful coordination of activity among molecules. Genes have to be expressed in the right cells at the right times, and the proteins that genes encode for must be properly folded into specific three-dimensional shapes so they will work properly. Proteins also usually have to go to the right places in cells to properly perform their function. Scientists have now learned more about how genetic mutations can cause proteins to end up in the wrong places, or mislocalize. This study has shown that about one in every six genetic mutations that is linked to disease causes a protein to end up in the wrong place in a cell. The findings have been reported in Cell.
Technological advances in genetic sequencing have allowed researchers to identify thousands of protein mutations that cause disease, noted first study author Jessica Lacoste, PhD, a postdoctoral researcher at the University of Toronto (U of T). "We are now able to identify these mutations in patients at the clinic, but we have no idea what their consequences are for cellular processes. This study was meant to help bridge that gap in knowledge."
Genetic mutations can lead to dysfunctional proteins in various ways; they might cause the protein's amino acid sequence to be too short, or too long, for example; or they may lead to problems with the three-dimensional structure of the protein. But genetic mutations can also cause proteins to mislocalize. In recent decades, scientists have learned more about mutations that impair protein structure or function, and less about those that cause mislocalization.
In this work, the researchers utilized powerful microscopy and computational tools to determine where mutated proteins ended up in the cell compared to their normal counterparts. Mislocalization was found to be more common that we have known. The primary cause of mislocalization seems to be impairments in a protein's ability to integrate into a membrane, and is not usually due to problems with protein interactions or stability.
"No one else has studied the impact of pathogenic missense mutations on a scale like this, where we've tracked the movement of proteins to different organelles," noted co-corresponding study author Mikko Taipale, a professor at U of T, among other appointments. "The patterns of mislocalization we've observed help explain disease severity caused by certain mutations and improve our understanding of mutations that were less studied."
For example, a common mutation associated with cystic fibrosis causes the mutant protein to go to an organelle called the endoplasmic reticulum, instead of the cell surface as it normally should.
There are some therapeutics that aim to restore proteins to their correct location and address the issues caused by mislocalization. But more focus on this issue appears to be needed.
"We've made our protein mislocalization database available as a comprehensive resource that can be used by other researchers to expand our collective knowledge on the effects of genetic variation on human disease," said co-corresponding study author Anne Carpenter, senior director of the Imaging Platform at the Broad Institute. "One particularly useful application of this data would be to identify compounds that could help mutant proteins localize correctly to treat rare diseases."
Sources: University of Toronto, Cell
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