Axonal Transport and Neurodegeneration: How Marine Drugs Can Be Used for the Development of Therapeutics

White, Joseph A.; Banerjee, Rupkatha; Gunawardena, Shermali

doi:10.3390/md14050102

Cited by 12 publications

(12 citation statements)

References 148 publications

(198 reference statements)

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“…Taken together, these semantic classes suggest the critical importance of elements of the cytoskeleton (as implied by the known genes MAPT and DCTN1 ) for the overall neuronal development and homeostasis as well as for the support of vesicle transport, likely indicating an effect on exo/endocytic as well as secretion (neurotransmission) pathways. 49 , 50 …”

Section: Resultsmentioning

confidence: 99%

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

Ferrari¹,

Lovering

Hardy³

et al. 2017

J. Proteome Res.

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The genetic analysis of complex disorders has undoubtedly led to the identification of a wealth of associations between genes and specific traits. However, moving from genetics to biochemistry one gene at a time has, to date, rather proved inefficient and under-powered to comprehensively explain the molecular basis of phenotypes. Here we present a novel approach, weighted protein–protein interaction network analysis (W-PPI-NA), to highlight key functional players within relevant biological processes associated with a given trait. This is exemplified in the current study by applying W-PPI-NA to frontotemporal dementia (FTD): We first built the state of the art FTD protein network (FTD-PN) and then analyzed both its topological and functional features. The FTD-PN resulted from the sum of the individual interactomes built around FTD-spectrum genes, leading to a total of 4198 nodes. Twenty nine of 4198 nodes, called inter-interactome hubs (IIHs), represented those interactors able to bridge over 60% of the individual interactomes. Functional annotation analysis not only reiterated and reinforced previous findings from single genes and gene-coexpression analyses but also indicated a number of novel potential disease related mechanisms, including DNA damage response, gene expression regulation, and cell waste disposal and potential biomarkers or therapeutic targets including EP300. These processes and targets likely represent the functional core impacted in FTD, reflecting the underlying genetic architecture contributing to disease. The approach presented in this study can be applied to other complex traits for which risk-causative genes are known as it provides a promising tool for setting the foundations for collating genomics and wet laboratory data in a bidirectional manner. This is and will be critical to accelerate molecular target prioritization and drug discovery.

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Section: Resultsmentioning

confidence: 99%

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

Ferrari¹,

Lovering

Hardy³

et al. 2017

J. Proteome Res.

View full text Add to dashboard Cite

show abstract

“…By contrast, the activation of autophagy might enhance disease severity during the late stages of AD, by accelerating Aβ-amyloid production.The autophagy–lysosome pathway is unable to “keep up” with the misfolded protein load that is built up, and becomes defective, causing the aggregation of protein [ 65 ]. A mutation in sequestosome1 (SQSTM1), a marker for autophagy that binds cargoes, is identified in patients with familial AD [ 66 ]. iv.…”

Section: Mild Cognitive Impairmentmentioning

confidence: 99%

“…Drug activities and drug mechanisms of action are investigated on cellular and/or in mouse model systems. Every marine bioactive compound is studied in a single disease (COPD or MCI/AD) model [ 66 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ].…”

Section: Mild Cognitive Impairmentmentioning

confidence: 99%

“…Bafilomycin(s), with chemical formula C 35 H 58 O 9 ( Figure 6 ), a family of toxic macrolide antibiotics from marine Streptomyces griseus , inhibits autophagy by preventing fusion of autophagosomes with lysosomes [ 66 ].…”

Section: Mild Cognitive Impairmentmentioning

confidence: 99%

“…Coibamide A, with chemical formula C 65 H 110 N 10 O 16 ( Figure 7 ), an antiproliferative depsipeptide isolated from a marine Leptolyngbya cyanobacterium, induces autophagy in an autophagy-related gene 5 ( Atg5 )-dependent manner [ 66 ].…”

Section: Mild Cognitive Impairmentmentioning

confidence: 99%

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Cognitive Impairment in Chronic Obstructive Pulmonary Disease (COPD): Possible Utility of Marine Bioactive Compounds

et al. 2018

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Chronic obstructive pulmonary disease (COPD) is characterized by long-term airflow limitation. Early-onset COPD in non-smoker subjects is ≥60 years and in the elderly is often associated with different comorbidities. Cognitive impairment is one of the most common feature in patients with COPD, and is associated with COPD severity and comorbidities. Cognitive impairment in COPD enhances the assistance requirement in different aspects of daily living, treatment adherence, and effectual self-management.This review describes various bioactive compounds of natural marine sources that modulate different targets shared by both COPD and cognitive impairment and hypothesizes a possible link between these two syndromes.

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Excess active P13K rescues huntingtin-mediated neuronal cell death but has no effect on axonal transport defects

et al. 2019

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High levels of oxidative stress is detected in neurons affected by many neurodegenerative diseases, including Huntington's disease (HD). Many of these diseases also show neuronal cell death and axonal transport defects. While nuclear inclusions/accumulations likely cause cell death, we previously showed that cytoplasmic axonal accumulations can also contribute to neuronal death. However, the cellular mechanisms responsible for activating cell death is unclear. One possibility is that perturbations in normal axonal transport alter the function of the phosphatidylinositol 3kinase (PI3K)-protein kinase B (AKT)-pathway, a signal transduction pathway that promotes survival/growth in response to extracellular signals. To test this proposal in vivo, we expressed active PI3K in the context of pathogenic huntingtin (HTT-138Q) in Drosophila larval nerves, which show axonal transport defects and neuronal cell death. We found that excess expression of active P13K significantly suppressed HTT-138Q-mediated neuronal cell death, but had no effect on HTT-138Q-mediated axonal transport defects. Expression of active PI3K also rescued Paraquat-mediated cell death. Further, increased levels of pSer9 (inactive) glycogen synthase kinase (GSK) 3β was seen in HTT-138Q-mediated larval brains, and in dynein loss of function mutants, indicating the modulation of the pro-survival pathway. Intriguingly, proteins in the PI3K/ AKT-pathway showed functional interactions with motor proteins. Taken together our observations suggest that proper axonal transport is likely essential for the normal function of the pro-survival PI3K/AKT-signaling pathway and for neuronal survival in vivo. These results have important implications for targeting therapeutics to early insults during neurodegeneration and death.

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Axonal Transport and Neurodegeneration: How Marine Drugs Can Be Used for the Development of Therapeutics

Cited by 12 publications

References 148 publications

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

Cognitive Impairment in Chronic Obstructive Pulmonary Disease (COPD): Possible Utility of Marine Bioactive Compounds

Excess active P13K rescues huntingtin-mediated neuronal cell death but has no effect on axonal transport defects

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