Neurodegenerative disease: models, mechanisms, and a new hope.
TL;DR: A new Special Collection, ‘Neurodegeneration: from models to mechanisms to therapies’ is introduced, providing a summary of the research and review articles published in this launch issue, as well as highlighting some of DMM's most-read neurodegenerative-related articles from recent issues.
Abstract: Neurodegeneration is a feature of many debilitating, incurable diseases that are rapidly rising in prevalence, such as Parkinson's disease. There is an urgent need to develop new and more effective therapeutic strategies to combat these devastating diseases. Models - from cell-based systems, to unicellular organisms, to complex animals - have proven to be a useful tool to help the research community shed light on the mechanisms underlying neurodegenerative diseases, and these advances have now begun to provide promising therapeutic avenues. In this themed issue of Disease Models & Mechanisms, a special collection of articles focused on neurodegenerative diseases is introduced. The collection includes original research articles that provide new insights into the complex pathophysiology of such diseases, revealing candidate biomarkers or therapeutic targets. Some of the articles describe a new disease model that enables deeper exploration of key mechanisms. We also present a series of reviews that highlight some of the recent translational advances made in studies of neurodegenerative diseases. In this Editorial, we summarize the articles featured in this collection, emphasizing the impact that model-based studies have made in this exciting area of research.
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TL;DR: In this article, Artificial Neural Networks and deep learning algorithms have been implemented in several drug discovery processes such as peptide synthesis, structure-based virtual screening, ligand-based screening, toxicity prediction, drug monitoring and release, pharmacophore modeling, quantitative structure-activity relationship, drug repositioning, polypharmacology, and physiochemical activity.
Abstract: Drug designing and development is an important area of research for pharmaceutical companies and chemical scientists. However, low efficacy, off-target delivery, time consumption, and high cost impose a hurdle and challenges that impact drug design and discovery. Further, complex and big data from genomics, proteomics, microarray data, and clinical trials also impose an obstacle in the drug discovery pipeline. Artificial intelligence and machine learning technology play a crucial role in drug discovery and development. In other words, artificial neural networks and deep learning algorithms have modernized the area. Machine learning and deep learning algorithms have been implemented in several drug discovery processes such as peptide synthesis, structure-based virtual screening, ligand-based virtual screening, toxicity prediction, drug monitoring and release, pharmacophore modeling, quantitative structure-activity relationship, drug repositioning, polypharmacology, and physiochemical activity. Evidence from the past strengthens the implementation of artificial intelligence and deep learning in this field. Moreover, novel data mining, curation, and management techniques provided critical support to recently developed modeling algorithms. In summary, artificial intelligence and deep learning advancements provide an excellent opportunity for rational drug design and discovery process, which will eventually impact mankind. The primary concern associated with drug design and development is time consumption and production cost. Further, inefficiency, inaccurate target delivery, and inappropriate dosage are other hurdles that inhibit the process of drug delivery and development. With advancements in technology, computer-aided drug design integrating artificial intelligence algorithms can eliminate the challenges and hurdles of traditional drug design and development. Artificial intelligence is referred to as superset comprising machine learning, whereas machine learning comprises supervised learning, unsupervised learning, and reinforcement learning. Further, deep learning, a subset of machine learning, has been extensively implemented in drug design and development. The artificial neural network, deep neural network, support vector machines, classification and regression, generative adversarial networks, symbolic learning, and meta-learning are examples of the algorithms applied to the drug design and discovery process. Artificial intelligence has been applied to different areas of drug design and development process, such as from peptide synthesis to molecule design, virtual screening to molecular docking, quantitative structure-activity relationship to drug repositioning, protein misfolding to protein-protein interactions, and molecular pathway identification to polypharmacology. Artificial intelligence principles have been applied to the classification of active and inactive, monitoring drug release, pre-clinical and clinical development, primary and secondary drug screening, biomarker development, pharmaceutical manufacturing, bioactivity identification and physiochemical properties, prediction of toxicity, and identification of mode of action.
211 citations
TL;DR: Findings suggest that rutin may be a promising neuroprotective compound for the treatment of NDs.
Abstract: A wide range of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases, share common mechanisms such as neuronal loss, apoptosis, mitochondrial dysfunction, oxidative stress, and inflammation. Intervention strategies using plant-derived bioactive compounds have been offered as a form of treatment for these debilitating conditions, as there are currently no remedies to prevent, reverse, or halt the progression of neuronal loss. Rutin, a glycoside of the flavonoid quercetin, is found in many plants and fruits, especially buckwheat, apricots, cherries, grapes, grapefruit, plums, and oranges. Pharmacological studies have reported the beneficial effects of rutin in many disease conditions, and its therapeutic potential in several models of NDs has created considerable excitement. Here, we have summarized the current knowledge on the neuroprotective mechanisms of rutin in various experimental models of NDs. The mechanisms of action reviewed in this article include reduction of proinflammatory cytokines, improved antioxidant enzyme activities, activation of the mitogen-activated protein kinase cascade, downregulation of mRNA expression of PD-linked and proapoptotic genes, upregulation of the ion transport and antiapoptotic genes, and restoration of the activities of mitochondrial complex enzymes. Taken together, these findings suggest that rutin may be a promising neuroprotective compound for the treatment of NDs.
206 citations
Cites background from "Neurodegenerative disease: models, ..."
...Neurodegenerative diseases (NDs) are regarded as an agerelated group of chronic and untreatable conditions which constitutes a major threat to human health [1]....
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...There are a number of NDs, but for the purposes of this review, we will focus on Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and human prion diseases (PrDs) [1, 12]....
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TL;DR: This Review reflects on five aspects critical for understanding how nature harnesses these noncanonical post-translational modifications to coordinate distinct cellular activities: specific players and their generation, physicochemical properties, mechanisms of action, methods of interrogation, and functional roles in health and disease.
Abstract: The concept of cell signaling in the context of nonenzyme-assisted protein modifications by reactive electrophilic and oxidative species, broadly known as redox signaling, is a uniquely complex topic that has been approached from numerous different and multidisciplinary angles. Our Review reflects on five aspects critical for understanding how nature harnesses these noncanonical post-translational modifications to coordinate distinct cellular activities: (1) specific players and their generation, (2) physicochemical properties, (3) mechanisms of action, (4) methods of interrogation, and (5) functional roles in health and disease. Emphasis is primarily placed on the latest progress in the field, but several aspects of classical work likely forgotten/lost are also recollected. For researchers with interests in getting into the field, our Review is anticipated to function as a primer. For the expert, we aim to stimulate thought and discussion about fundamentals of redox signaling mechanisms and nuances of sp...
204 citations
TL;DR: There is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years.
Abstract: Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments available only manage the symptoms or halt the progression of the disease. Therefore, there is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years. New therapies can come from three main sources: synthesis, natural products, and existing drugs. This last source is known as drug repurposing, which is the most advantageous, since the drug’s pharmacokinetic and pharmacodynamic profiles are already established, and the investment put into this strategy is not as significant as for the classic development of new drugs. There have been several studies on the potential of old drugs for the most relevant neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.
197 citations
Cites background from "Neurodegenerative disease: models, ..."
...The need for treatment for NDs is urgent, since the World Health Organization (WHO) predicts that in 20 years, NDs that mainly affect motor functions will overtake cancer to become the second‐most prevalent cause of death, after cardiovascular diseases [9,10]....
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...The need for treatment for NDs is urgent, since the World Health Organization (WHO) predicts that in 20 years, NDs that mainly affect motor functions will overtake cancer to become the second-most prevalent cause of death, after cardiovascular diseases [9,10]....
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TL;DR: The authors reviewed similarities and differences among four main proteins, α-synuclein, FUS, tau, and TDP-43, which are found aggregated in different diseases and were independently shown to phase separate.
177 citations
References
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TL;DR: Onset and progression of amyotrophic lateral sclerosis represent distinct disease phases defined by mutant action within different cell types to generate non–cell-autonomous killing of motor neurons; these findings validate therapies, including cell replacement, targeted to the non-neuronal cells.
Abstract: Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression. Onset and progression thus represent distinct disease phases defined by mutant action within different cell types to generate non-cell-autonomous killing of motor neurons; these findings validate therapies, including cell replacement, targeted to the non-neuronal cells.
1,538 citations
"Neurodegenerative disease: models, ..." refers background in this paper
...…for many years to study neurodegenerative diseases and have provided key insights into disease mechanisms (Link, 1995; Krobitsch and Lindquist, 2000; Boillee et al., 2006; Bruijn et al., 1998; Yamamoto et al., 2000; Auluck et al., 2002; Outeiro and Lindquist, 2003; Cooper et al., 2006; Gitler et…...
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TL;DR: Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified, and emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid-liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.
1,382 citations
"Neurodegenerative disease: models, ..." refers background in this paper
...These diseases are diverse in their pathophysiology – with some causing memory and cognitive impairments and others affecting a person’s ability to move, speak and breathe (Abeliovich and Gitler, 2016; Canter et al., 2016; Taylor et al., 2016; Wyss-Coray, 2016)....
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TL;DR: Elevated expression of Rab1, the mammalian YPT1 homolog, protected against αSyn-induced dopaminergic neuron loss in animal models of PD, suggesting synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.
Abstract: Alpha-synuclein (αSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson9s disease (PD). In yeast cells and in neurons αSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following αSyn expression in yeast was a block in endoplasmic reticulum (ER)–to–Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic αSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against αSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.
1,314 citations
"Neurodegenerative disease: models, ..." refers background in this paper
...…Krobitsch and Lindquist, 2000; Boillee et al., 2006; Bruijn et al., 1998; Yamamoto et al., 2000; Auluck et al., 2002; Outeiro and Lindquist, 2003; Cooper et al., 2006; Gitler et al., 2008, 2009; Elden et al., 2010; Couthouis et al., 2011; Armakola et al., 2012; Jovičic ́ et al., 2015; Becker…...
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TL;DR: Analysis of transgenic mice expressing familial amyotrophic lateral sclerosis (ALS)-linked mutations in the enzyme superoxide dismutase (SOD1) have shown that motor neuron death arises from a mutant-mediated toxic property or properties, raising the question of whether toxicity arises from superoxide-mediated oxidative stress.
Abstract: Analysis of transgenic mice expressing familial amyotrophic lateral sclerosis (ALS)-linked mutations in the enzyme superoxide dismutase (SOD1) have shown that motor neuron death arises from a mutant-mediated toxic property or properties. In testing the disease mechanism, both elimination and elevation of wild-type SOD1 were found to have no effect on mutant-mediated disease, which demonstrates that the use of SOD mimetics is unlikely to be an effective therapy and raises the question of whether toxicity arises from superoxide-mediated oxidative stress. Aggregates containing SOD1 were common to disease caused by different mutants, implying that coaggregation of an unidentified essential component or components or aberrant catalysis by misfolded mutants underlies a portion of mutant-mediated toxicity.
1,198 citations
"Neurodegenerative disease: models, ..." refers background in this paper
...Powerful experimental model organisms such as the mouse, fruit fly, nematode worm, and even baker’s yeast have been used for many years to study neurodegenerative diseases and have provided key insights into disease mechanisms (Link, 1995; Krobitsch and Lindquist, 2000; Boillee et al., 2006; Bruijn et al., 1998; Yamamoto et al., 2000; Auluck et al., 2002; Outeiro and Lindquist, 2003; Cooper et al., 2006; Gitler et al., 2008, 2009; Elden et al., 2010; Couthouis et al., 2011; Armakola et al., 2012; Jovičic ́ et al., 2015; Becker et al., 2017)....
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...…neurodegenerative diseases and have provided key insights into disease mechanisms (Link, 1995; Krobitsch and Lindquist, 2000; Boillee et al., 2006; Bruijn et al., 1998; Yamamoto et al., 2000; Auluck et al., 2002; Outeiro and Lindquist, 2003; Cooper et al., 2006; Gitler et al., 2008, 2009; Elden…...
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TL;DR: Direct expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with α-synuclein in Drosophila and that interference with endogenous chaper one activity accelerated α- synuclein toxicity, suggesting chaperones may play a role in Parkinson's disease progression.
Abstract: Parkinson's disease is a movement disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic neuronal loss also occurs in Drosophila melanogaster upon directed expression of alpha-synuclein, a protein implicated in the pathogenesis of Parkinson's disease and a major component of proteinaceous Lewy bodies. We report that directed expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with alpha-synuclein in Drosophila and that interference with endogenous chaperone activity accelerated alpha-synuclein toxicity. Furthermore, Lewy bodies in human postmortem tissue immunostained for molecular chaperones, also suggesting that chaperones may play a role in Parkinson's disease progression.
1,175 citations
"Neurodegenerative disease: models, ..." refers background in this paper
...…key insights into disease mechanisms (Link, 1995; Krobitsch and Lindquist, 2000; Boillee et al., 2006; Bruijn et al., 1998; Yamamoto et al., 2000; Auluck et al., 2002; Outeiro and Lindquist, 2003; Cooper et al., 2006; Gitler et al., 2008, 2009; Elden et al., 2010; Couthouis et al., 2011;…...
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