Saccharomyces cerevisiae
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA270712 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Parkinson's disease (PD) is a common human neurodegenerative movement disorder. Studies of the genetic forms of PD have helped to reveal disease mechanisms. Functional interactions between some Parkinson's disease (PD) genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1 and alpha-synuclein, a protein with a key role in the pathogenesis of both sporadic and familial PD. We extend our findings from yeast to an animal model and show these interactions are conserved in neurons. We also connect VPS35 impairments to neurodegeneration in alpha-synuclein transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future genetic and functional interrogation. Ribosome profiling (RiboSeq) of wild type and VPS35 deletion yeast strains, with or without overexpression of the TIF4631 initiation factor
2014-12-19 | E-GEOD-64304 | biostudies-arrayexpress
Project description:Parkinson's disease (PD) is a common human neurodegenerative movement disorder. Studies of the genetic forms of PD have helped to reveal disease mechanisms. Functional interactions between some Parkinson's disease (PD) genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1 and alpha-synuclein, a protein with a key role in the pathogenesis of both sporadic and familial PD. We extend our findings from yeast to an animal model and show these interactions are conserved in neurons. We also connect VPS35 impairments to neurodegeneration in alpha-synuclein transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future genetic and functional interrogation.
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Project description:Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. Functional and causal pathway analysis of gene expression and proteomic alterations in these three regions revealed pathways that correlated with deposition of alpha-synuclein. Microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release and other changes were reflected across all brain regions. Importantly a subset of these changes were replicated in Parkinson's disease blood. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany alpha-synculein pathology in Parkinson's disease, and may be instrumental in understanding and diagnosing Parkinson's disease progression. Substantia Nigra (3 normal, 3 PD), Striatum (6 normal, 6 PD), Cortex (5 normal, 5 PD), Cortex non-PD neurodegeneration (2 normal, 3 DLB). Note Sample X201264 was used both for Cortex normal and for Cortex nonPD normal
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Project description:Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. Functional and causal pathway analysis of gene expression and proteomic alterations in these three regions revealed pathways that correlated with deposition of alpha-synuclein. Microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release and other changes were reflected across all brain regions. Importantly a subset of these changes were replicated in Parkinson's disease blood. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany alpha-synculein pathology in Parkinson's disease, and may be instrumental in understanding and diagnosing Parkinson's disease progression.
2014-09-01 | GSE54282 | GEO
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Project description:The pre-synaptic protein α-synuclein is a key player in the pathogenesis of Parkinson's disease. Together with accumulation and missfolding of α-synuclein protofibrils serve as seed structures for the aggregation of numerous proteins in the cytoplasm of neuronal cells, the so-called Lewy bodies. Furthermore, missense mutations in the SNCA gene and gene multiplications lead to autosomal dominant forms of familiar PD. However, so far the exact biological role of α-synuclein in normal brain is elusive. To gain more insights into the biological function of this protein we monitored whole genome expression changes in dopaminergic neuroblastoma cells (SH-SY5Y) caused by a 90% reduction of α-synuclein by RNA interference. Keywords: whole genome expression changes through the loss of α-synuclein
2009-02-01 | GSE9807 | GEO
Project description:Sass2009 - Approach to an
α-synuclein-based BST model of Parkinson's disease
This model is described in the article:
A pragmatic approach to
biochemical systems theory applied to an alpha-synuclein-based
model of Parkinson's disease.
Sass MB, Lorenz AN, Green RL,
Coleman RA.
J. Neurosci. Methods 2009 Apr; 178(2):
366-377
Abstract:
This paper presents a detailed systems model of Parkinson's
disease (PD), developed utilizing a pragmatic application of
biochemical systems theory (BST) intended to assist
experimentalists in the study of system behavior. This approach
utilizes relative values as a reasonable initial estimate for
BST and provides a theoretical means of applying numerical
solutions to qualitative and semi-quantitative understandings
of cellular pathways and mechanisms. The approach allows for
the simulation of human disease through its ability to organize
and integrate existing information about metabolic pathways
without having a full quantitative description of those
pathways, so that hypotheses about individual processes may be
tested in a systems environment. Incorporating this method, the
PD model describes alpha-synuclein aggregation as mediated by
dopamine metabolism, the ubiquitin-proteasome system, and
lysosomal degradation, allowing for the examination of dynamic
pathway interactions and the evaluation of possible toxic
mechanisms in the aggregation process. Four system
perturbations: elevated alpha-synuclein aggregation, impaired
dopamine packaging, increased neurotoxins, and alpha-synuclein
overexpression, were analyzed for correlation to qualitative PD
system hypotheses present in the literature, with the model
demonstrating a high level of agreement with these hypotheses.
Additionally, various PD treatment methods, including levadopa
and monoamine oxidase inhibition (MAOI) therapy, were applied
to the disease models to examine their effects on the system.
Future additions and refinements to the model may further the
understanding of the emergent behaviors of the disease, helping
in the identification of system sensitivities and possible
therapeutic targets.
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2015-04-13 | BIOMD0000000575 | BioModels