HtrA1 prevents and reverses α-synuclein aggregation, rendering it non-toxic and seeding incompetent
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: Meredith E. Jackrel
PROVIDER: PXD041784 | JPOST Repository | Tue Feb 20 00:00:00 GMT 2024
REPOSITORIES: jPOST
Dataset's files
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| 01aSYNs1.raw | Raw | |||
| 01aSYNs1s2.raw | Raw | |||
| 02aSYNs2.raw | Raw | |||
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| 02aSYNs4.raw | Raw |
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Similar Datasets
Project description:Parkinson disease (PD) is closely linked to the misfolding and accumulation of α-synuclein (α-syn) into Lewy bodies. HTRA1 is a PDZ serine protease that degrades fibrillar tau, which is associated with Alzheimer disease (AD). Further, inactivating mutations to mitochondrial HTRA2 have been implicated in PD. Here, we establish that HTRA1 inhibits the aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We demonstrate that the protease domain of HTRA1 is necessary and sufficient for inhibition of aggregation, yet this activity is independent of HTRA1 proteolytic activity. Further, we find that HTRA1 also disaggregates preformed α-syn fibrils, which may promote their clearance. Treatment of α-syn fibrils with HTRA1 renders α-syn incapable of seeding the aggregation of endogenous α-syn in mammalian biosensor cells. We find that HTRA1 remodels α-syn by specifically targeting the NAC domain, which is the key domain that catalyzes α-syn oligomerization and fibrillization. Finally, in a primary neuron model of α-syn aggregation, we show that HTRA1 and its proteolytically inactive form both detoxify α-syn and prevent the formation of hyperphosphorylated α-syn accumulations. Our findings suggest that HTRA1 prevents aggregation and promotes disaggregation of multiple disease-associated proteins, and may be a therapeutic target for treating a range of neurodegenerative disorders.
2024-02-20 | PXD044806 | JPOST Repository
Project description:Kuznetsov2016(II) - α-syn aggregation
kinetics in Parkinson's
This theoretical model uses 2-step Finke-Watzky (FW) kinetics
todescribe the production, misfolding, aggregation, transport and
degradation of α-syn that may lead to Parkinson's Disease
(PD). Deregulated α-syn degradation is predicted to be
crucialfor PD pathogenesis.
This model is described in the article:
What can trigger the onset
of Parkinson's disease - A modeling study based on a
compartmental model of α-synuclein transport and aggregation in
neurons.
Kuznetsov IA, Kuznetsov AV.
Math Biosci 2016 Aug; 278: 22-29
Abstract:
The aim of this paper is to develop a minimal model
describing events leading to the onset of Parkinson's disease
(PD). The model accounts for α-synuclein (α-syn) production in
the soma, transport toward the synapse, misfolding, and
aggregation. The production and aggregation of polymeric α-syn
is simulated using a minimalistic 2-step Finke-Watzky model. We
utilized the developed model to analyze what changes in a
healthy neuron are likely to lead to the onset of α-syn
aggregation. We checked the effects of interruption of α-syn
transport toward the synapse, entry of misfolded (infectious)
α-syn into the somatic and synaptic compartments, increasing
the rate of α-syn synthesis in the soma, and failure of α-syn
degradation machinery. Our model suggests that failure of α-syn
degradation machinery is probably the most likely cause for the
onset of α-syn aggregation leading to PD.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000615.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000615 | BioModels
Project description:Genetic polymorphisms in the region of the trimeric serine hydrolase HTRA1 are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remains undefined. In this study, we have developed an HtrA1 blocking Fab fragment to test the therapeutic hypothesis that HtrA1 protease activity is involved in the progression of AMD. Next, we generated an activity-based small molecule probe (ABP) to track target engagement in vivo. In addition, we used N-terminomic proteomic profiling in pre-clinical models to elucidate the in vivo repertoire of HtrA1 specific substrates, and identified substrates that can serve as robust pharmacodynamic biomarkers of HtrA1 activity. One of these HtrA1 substrates, Dickkopf related protein 3 (DKK3), was successfully used as a biomarker to demonstrate the inhibition of HtrA1 activity in patients with AMD that were treated with the HtrA1 blocking Fab fragment. To our knowledge, this is the first pharmacodynamic biomarker measuring ocular protease activity in AMD.
2020-01-22 | MSV000084831 | MassIVE
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.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000575.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000575 | BioModels
Project description:Parkinson disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (SNCA) and other proteins in aggregates termed âLewy Bodiesâ within neurons. PD has both genetic and environmental risk factors, and while processes leading to aberrant protein aggregation are unknown, past work points to abnormal levels of SNCA and other proteins. Although several genome-wide studies have been performed for PD, these have focused on DNA sequence variants by genome-wide association studies (GWAS) and on RNA levels (microarray transcriptomics), while genome-wide proteomics analysis has been lacking. After appropriate filters, proteomics identified 3,558 unique proteins and 283 of these (7.9%) were significantly different between PD and controls (q-value<0.05). RNA-sequencing identified 17,580 protein-coding genes and 1,095 of these (6.2%) were significantly different (FDR p-value<0.05), but only 166 of the FDR significant protein-coding genes (0.94%) were present among the 3,558 proteins characterized. Of these 166, eight genes (4.8%) were significant in both studies, with the same direction of effect. Functional enrichment analysis of the proteomics results strongly supports mitochondrial-related pathways, while comparable analysis of the RNA-sequencing results implicates protein folding pathways and metallothioneins. Ten of the implicated genes or proteins co-localized to GWAS loci. Evidence implicating SNCA was stronger in proteomics than in RNA-sequencing analyses. Notably, differentially expressed protein-coding genes were more likely to not be characterized in the proteomics analysis, which lessens the ability to compare across platforms. Combining multiple genome-wide platforms offers novel insights into the pathological processes responsible for this disease by identifying pathways implicated across methodologies. The study consists of mRNA-Seq (29 PD, 44 neurologically normal controls) and three-stage Mass Spectrometry Tandem Mass Tag Proteomics (12 PD, 12 neurologically normal controls) performed in post-mortem BA9 brain tissue. The proteomics samples are a subset of the RNA-Seq samples.
2016-01-15 | E-GEOD-68719 | biostudies-arrayexpress
Project description:Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson’s disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6,215 proteins and 1.6% of 8,183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders.
2018-05-18 | PXD009647 | Pride
Project description:Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson’s disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6,215 proteins and 1.6% of 8,183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders.
2018-05-18 | PXD009717 | Pride
Project description:Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson’s disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6,215 proteins and 1.6% of 8,183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders.
2018-05-18 | PXD009718 | Pride
Project description:Sneppen2009 - Modeling proteasome dynamics in
Parkinson's disease
This model is described in the article:
Modeling proteasome dynamics
in Parkinson's disease.
Sneppen K, Lizana L, Jensen MH,
Pigolotti S, Otzen D.
Phys Biol 2009; 6(3): 036005
Abstract:
In Parkinson's disease (PD), there is evidence that
alpha-synuclein (alphaSN) aggregation is coupled to
dysfunctional or overburdened protein quality control systems,
in particular the ubiquitin-proteasome system. Here, we develop
a simple dynamical model for the on-going conflict between
alphaSN aggregation and the maintenance of a functional
proteasome in the healthy cell, based on the premise that
proteasomal activity can be titrated out by mature alphaSN
fibrils and their protofilament precursors. In the presence of
excess proteasomes the cell easily maintains homeostasis.
However, when the ratio between the available proteasome and
the alphaSN protofilaments is reduced below a threshold level,
we predict a collapse of homeostasis and onset of oscillations
in the proteasome concentration. Depleted proteasome opens for
accumulation of oligomers. Our analysis suggests that the onset
of PD is associated with a proteasome population that becomes
occupied in periodic degradation of aggregates. This behavior
is found to be the general state of a proteasome/chaperone
system under pressure, and suggests new interpretations of
other diseases where protein aggregation could stress elements
of the protein quality control system.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000548.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000548 | BioModels
Project description:A key process of neurodegeneration in Parkinson's disease (PD) is the transneuronal spreading of alpha-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of a-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of alpha-synuclein induced by intracerebral injection of a-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for a-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also withouta-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that a-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric a-synuclein species, which induce unusual microglial reactivity, play a key role in this process.
2020-11-02 | GSE155716 | GEO