HDNetDB: A Molecular Interaction Database for Network-Oriented Investigations into Huntington’s Disease

Kalathur, Ravi Kiran Reddy; Pinto, José P.; Sahoo, B. B.; Chaurasia, Gautam; Futschik, Matthias E.

doi:10.1038/s41598-017-05224-0

Cited by 21 publications

(12 citation statements)

References 92 publications

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“…It is thought that HTT acts as a scaffolding protein [27,28] , involved in many protein-protein interactions and the formation of multi-protein complexes. Dysregulation of this interaction network by the polyQ expansion and subsequent aggregation is thought to be responsible for the resultant phenotype [29,30] , sometimes described as a gain-of-function. Most published work to date on HTT oligomers and their associated neuropathology has focussed on the so-called exon 1 proteins [31,32] .…”

Section: Acta Pharmacologica Sinicamentioning

confidence: 99%

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Harding

Tong

2018

Acta Pharmacol Sin

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Many neurodegenerative diseases are characterized by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons. Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington's disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular, the ubiquitin-proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides new insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review.

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Section: Acta Pharmacologica Sinicamentioning

confidence: 99%

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Harding

Tong

2018

Acta Pharmacol Sin

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“…As a result, specialized interaction networks that are related to human amyloids were published [130,131]. …”

Section: Methods For Investigation Of the Amyloid Interactomementioning

confidence: 99%

Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification

Bondarev

Antonets

Kajava

et al. 2018

IJMS

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Amyloids are unbranched protein fibrils with a characteristic spatial structure. Although the amyloids were first described as protein deposits that are associated with the diseases, today it is becoming clear that these protein fibrils play multiple biological roles that are essential for different organisms, from archaea and bacteria to humans. The appearance of amyloid, first of all, causes changes in the intracellular quantity of the corresponding soluble protein(s), and at the same time the aggregate can include other proteins due to different molecular mechanisms. The co-aggregation may have different consequences even though usually this process leads to the depletion of a functional protein that may be associated with different diseases. The protein co-aggregation that is related to functional amyloids may mediate important biological processes and change of protein functions. In this review, we survey the known examples of the amyloid-related co-aggregation of proteins, discuss their pathogenic and functional roles, and analyze methods of their studies from bacteria and yeast to mammals. Such analysis allow for us to propose the following co-aggregation classes: (i) titration: deposition of soluble proteins on the amyloids formed by their functional partners, with such interactions mediated by a specific binding site; (ii) sequestration: interaction of amyloids with certain proteins lacking a specific binding site; (iii) axial co-aggregation of different proteins within the same amyloid fibril; and, (iv) lateral co-aggregation of amyloid fibrils, each formed by different proteins.

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“…Therefore, NDs are a group of pathologically distinct but related diseases and two different directions have been used to investigate NDs using PPI networks by either focusing on a specific ND or analyzing a group of NDs, with the majority considering a specific disease [66][67][68]. The few studies that have investigated a group of NDs have primarily concentrated in identifying common molecular mechanisms by identifying direct protein/genes commonalities and pathways among NDs and indirect network relationships between NDs via topological association by identifying common modules in these diseases [69][70][71][72].…”

Section: Computational Analysis Of Virus-host-disease Ppis Using a Knmentioning

confidence: 99%

Identification of viral-mediated pathogenic mechanisms in neurodegenerative diseases using network-based approaches

Onisiforou

Spyrou

2020

Preprint

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During the course of a viral infection, virus-host protein-protein interactions (PPIs) play a critical role in allowing viruses to evade host immune responses, replicate and hence survive within the host. These interspecies molecular interactions can lead to viral-mediated perturbations of the human interactome causing the generation of various complex diseases, from cancer to neurodegenerative diseases (NDs). There are evidences suggesting that viral-mediated perturbations are a possible pathogenic aetiology in several NDs such as Amyloid Later Sclerosis, Parkinson’s disease, Alzheimer’s disease and Multiple Sclerosis (MS), as they can cause degeneration of neurons via both direct and/or indirect actions. These diseases share several common pathological mechanisms, as well as unique disease mechanisms that reflect disease phenotype. NDs are chronic degenerative diseases of the central nervous system and current therapeutic approaches provide only mild symptomatic relief rather than treating the disease at heart, therefore there is unmet need for the discovery of novel therapeutic targets and pharmacotherapies. In this paper we initially review databases and tools that can be utilized to investigate viral-mediated perturbations in complex NDs using network-based analysis by examining the interaction between the ND-related PPI disease networks and the virus-host PPI network. Afterwards we present our integrative network-based bioinformatics approach that accounts for pathogen-genes-disease related PPIs with the aim to identify viral-mediated pathogenic mechanisms focusing in MS disease. We identified 7 high centrality nodes that can act as disease communicator nodes and exert systemic effects in the MS enriched KEGG pathways network. In addition, we identified 12 KEGG pathways targeted by 67 viral proteins from 8 viral species that might exert viral-mediated pathogenic mechanisms in MS by interacting with the disease communicator nodes. Finally, our analysis highlighted the Th17 differentiation pathway, a hub-bottleneck disease communicator node and part of the 12 underlined KEGG pathways, as a key viral-mediated pathogenic mechanism and a possible therapeutic target for MS disease.

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HDNetDB: A Molecular Interaction Database for Network-Oriented Investigations into Huntington’s Disease

Cited by 21 publications

References 92 publications

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification

Identification of viral-mediated pathogenic mechanisms in neurodegenerative diseases using network-based approaches

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