Polyglutamine diseases: looking beyond the neurodegenerative universe.
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ABSTRACT:
SUBMITTER: Mielcarek M
PROVIDER: S-EPMC8224133 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Deposits of misfolded proteins in the human brain are associated with the development of many neurodegenerative diseases. Recent studies show that these proteins have common traits even at the monomer level. Among them, a polyglutamine region that is present in huntingtin is known to exhibit a correlation between the length of the chain and the severity as well as the earliness of the onset of Huntington disease. Here, we apply bias exchange molecular dynamics to generate structures of polyglutamine expansions of several lengths and characterize the resulting independent conformations. We compare the properties of these conformations to those of the standard proteins, as well as to other homopolymeric tracts. We find that, similar to the previously studied polyvaline chains, the set of possible transient folds is much broader than the set of known-to-date folds, although the conformations have different structures. We show that the mechanical stability is not related to any simple geometrical characteristics of the structures. We demonstrate that long polyglutamine expansions result in higher mechanical stability than the shorter ones. They also have a longer life span and are substantially more prone to form knotted structures. The knotted region has an average length of 35 residues, similar to the typical threshold for most polyglutamine-related diseases. Similarly, changes in shape and mechanical stability appear once the total length of the peptide exceeds this threshold of 35 glutamine residues. We suggest that knotted conformers may also harm the cellular machinery and thus lead to disease.
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Project description:The complex network of malfunctioning pathways occurring in the pathogenesis of neurodegenerative diseases (NDDs) represents a huge hurdle in the development of new effective drugs to be used in therapy. In this context, redox reactions act as crucial regulators in the maintenance of neuronal microenvironment homeostasis. Particularly, their imbalance results in the severe compromising of organism's natural defense systems and subsequently, in the instauration of deleterious OS, that plays a fundamental role in the insurgence and progress of NDDs. Despite the huge efforts in drug discovery programs, the identification process of new therapeutic agents able to counteract the relentless progress of neurodegenerative processes has produced low or no effective therapies. Consequently, a paradigm-shift in the drug discovery approach for these diseases is gradually occurring, paving the way for innovative therapeutical approaches, such as polypharmacology. The aim of this review is to provide an overview of the main pharmacological features of most promising nature-based scaffolds for a possible application in drug discovery, especially for NDDs, highlighting their multifaceted effects against OS and neuronal disorders.
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Project description:This study investigated the molecular spectrum of amyloid-beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease (AD). We analyzed Aβ deposition in the temporal cortex and striatum in 116 autopsies, including Lewy body disease (LBD; N = 51), multiple system atrophy (MSA; N = 10), frontotemporal lobar degeneration-TDP-43 (FTLD-TDP; N = 16), and progressive supranuclear palsy (PSP; N = 39). The LBD group exhibited the most Aβ deposition in the temporal cortex and striatum (90/76%, respectively), followed by PSP (69/28%), FTLD-TDP (50/25%), and the MSA group (50/10%). We conducted immunohistochemical analysis using antibodies targeting eight Aβ epitopes in the LBD and PSP groups. Immunohistochemical findings were evaluated semi-quantitatively and quantitatively using digital pathology. Females with LBD exhibited significantly more severe Aβ deposition, particularly Aβ42 and Aβ43 , along with significantly more severe tau pathology. Furthermore, a quantitative analysis of all Aβ peptides in the LBD group revealed an association with the APOE-ε4 genotypes. No significant differences were observed between males and females in the PSP group. Finally, we compared striatal Aβ deposition in cases with LBD (N = 15), AD without α-synuclein pathology (N = 6), and PSP (N = 5). There were no differences in the pan-Aβ antibody (6F/3D)-immunolabeled deposition burden among the three groups, but the deposition burden of peptides with high aggregation capacity, especially Aβ43 , was significantly higher in the AD and LBD groups than in the PSP group. Furthermore, considerable heterogeneity was observed in the composition of Aβ peptides on a case-by-case basis in the AD and LBD groups, whereas it was relatively uniform in the PSP group. Cluster analysis further supported these findings. Our data suggest that the type of concomitant proteinopathies influences the spectrum of Aβ deposition, impacted also by sex and APOE genotypes.
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Project description:The extracellular matrix (ECM) is a diverse microenvironment that maintains bidirectional communication with surrounding cells to regulate cell and tissue homeostasis. The classical definition of the ECM has more recently been extended to include non-fibrillar proteins that either interact or are structurally affiliated with the ECM, termed the 'matrisome.' In addition to providing the structure and architectural support for cells and tissue, the matrisome serves as a reservoir for growth factors and cytokines, as well as a signaling hub via which cells can communicate with their environment and vice-versa. The matrisome is a master regulator of tissue homeostasis and organ function, which can dynamically and appropriately respond to any stress or injury. Failure to properly regulate these responses can lead to changes in the matrisome that are maladaptive. Hepatic fibrosis is a canonical example of ECM dyshomeostasis, leading to accumulation of predominantly collagenous ECM; indeed, hepatic fibrosis is considered almost synonymous with collagen accumulation. However, the qualitative and quantitative alterations of the hepatic matrisome during fibrosis are much more diverse than simple accumulation of collagens and occur long before fibrosis is histologically detected. A deeper understanding of the hepatic matrisome and its response to injury could yield new mechanistic insights into disease progression and regression, as well as potentially identify new biomarkers for both. In this review, we discuss the role of the ECM in liver diseases and look at new "omic" approaches to study this compartment.
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Project description:Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity and inflammation are observed in most, if not all, neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data for Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease and schizophrenia using an extensive cohort of well characterised post-mortem CNS tissues. The analysis of whole genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease specific changes, but more importantly to uncover potential common molecular pathogenic mechanisms that could be targeted for therapeutic gain. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all 6 diseases using our primary method of analysis. However, 61 dysregulated genes were shared when comparing five and four diseases. Our analysis indicates firstly the involvement of common neuronal homeostatic, survival and synaptic plasticity pathways. Secondly, we report changes to immunoregulatory and immunomodulatory pathways in all diseases. Our secondary method of analysis confirmed significant up-regulation of a number of genes in diseases presenting degeneration and showed that somatostatin was downregulated in all 6 diseases. The latter is supportive of a general role for neuroinflammation in the pathogenesis and/or response to neurodegeneration. Unravelling the detailed nature of the molecular changes regulating inflammation in the CNS is key to the development of novel therapeutic approaches for these chronic conditions. A total of 113 cases were selected retrospectively on the basis of a confirmed clinical and neuropathological diagnosis and snap-frozen brain blocks were provided by various tissue banks within the BrainNet Europe network. Total RNA was extracted from dissected snap-frozen tissue (< 100 mg) by the individual laboratories according to a BNE optimised common protocol using the RNeasy(r) tissue lipid mini kit (Qiagen Ltd, Crawley, UK) according to the manufacturer's instructions, and was stored at -80C until further use. Gene expression analysis was performed on the RNA samples using the Illumina whole genome HumanRef8 v2 BeadChip (Illumina, London, UK). All the labelling and hybridisation of the samples was carried out in a single experiment by the Imperial College group to reduce the technical variability. RNA samples were prepared for array analysis using the Illumina TotalPrep(tm)-96 RNA Amplification Kit (Ambion/Applied Biosystems, Warrington, UK). Finally, the BeadChips we re scanned using the Illumina BeadArray Reader. The data was extracted using BeadStudio 3.2 (Illumina). Data normalisation and gene differential expression analyses were conducted using the Rosetta error models available in the Rosetta Resolver(r) system (Rosetta Biosoftware, Seattle, Wa, USA). Two samples presented very low signal expression most likely due to hybridization problems and did not pass the quality control test. They are not represented here. One of the 2 samples was a replicate, therefore there was loss of only 1 case bringing the grand total of cases used to 112 (total of samples of 118 including 6 replicates).
2011-01-29 | E-GEOD-26927 | biostudies-arrayexpress
Project description:PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.
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Project description:Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion. This can be either due to intrinsic modulation of aggregation by the flanking regions, or due to differential interaction with other proteins, such as the components of the cellular protein quality control network. Indeed, several lines of evidence suggest that molecular chaperones have impact on the handling of different polyQ proteins. Here, we review factors differentially influencing polyQ aggregation: the Q-stretch itself, modulatory flanking sequences, interaction partners, cleavage of polyQ-containing proteins, and post-translational modifications, with a special focus on the role of molecular chaperones. By discussing typical examples of how these factors influence aggregation, we provide more insight on the variability of AO between different diseases as well as within the same polyQ disorder, on the molecular level.
| S-EPMC5362620 | biostudies-literature
Project description:Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity and inflammation are observed in most, if not all, neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data for Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease and schizophrenia using an extensive cohort of well characterised post-mortem CNS tissues. The analysis of whole genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease specific changes, but more importantly to uncover potential common molecular pathogenic mechanisms that could be targeted for therapeutic gain. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all 6 diseases using our primary method of analysis. However, 61 dysregulated genes were shared when comparing five and four diseases. Our analysis indicates firstly the involvement of common neuronal homeostatic, survival and synaptic plasticity pathways. Secondly, we report changes to immunoregulatory and immunomodulatory pathways in all diseases. Our secondary method of analysis confirmed significant up-regulation of a number of genes in diseases presenting degeneration and showed that somatostatin was downregulated in all 6 diseases. The latter is supportive of a general role for neuroinflammation in the pathogenesis and/or response to neurodegeneration. Unravelling the detailed nature of the molecular changes regulating inflammation in the CNS is key to the development of novel therapeutic approaches for these chronic conditions.
2011-01-29 | GSE26927 | GEO
Project description:It is currently believed that the atlas of existing protein structures is faithfully represented in the Protein Data Bank. However, whether this atlas covers the full universe of all possible protein structures is still a highly debated issue. By using a sophisticated numerical approach, we performed an exhaustive exploration of the conformational space of a 60 amino acid polypeptide chain described with an accurate all-atom interaction potential. We generated a database of around 30,000 compact folds with at least of secondary structure corresponding to local minima of the potential energy. This ensemble plausibly represents the universe of protein folds of similar length; indeed, all the known folds are represented in the set with good accuracy. However, we discover that the known folds form a rather small subset, which cannot be reproduced by choosing random structures in the database. Rather, natural and possible folds differ by the contact order, on average significantly smaller in the former. This suggests the presence of an evolutionary bias, possibly related to kinetic accessibility, towards structures with shorter loops between contacting residues. Beside their conceptual relevance, the new structures open a range of practical applications such as the development of accurate structure prediction strategies, the optimization of force fields, and the identification and design of novel folds.
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