Biological metals and metal-targeting compounds in major neurodegenerative diseases.

Neurodegenerative diseases (NDDs) causing cognitive impairment and dementia are difficult to treat due to the lack of understanding of primary initiating factors. Meanwhile, major sporadic NDDs share many risk factors and exhibit similar pathologies in their early stages, indicating the existence of common initiation pathways. Glucose hypometabolism associated with oxidative stress is one such primary, early and shared pathology, and a likely major cause of detrimental disease-associated cascades; targeting this common pathology may therefore be an effective preventative strategy for most sporadic NDDs. However, its exact cause and trigger remain unclear. Recent research suggests that early oxidative stress caused by NADPH oxidase (NOX) activation is a shared initiating mechanism among major sporadic NDDs and could prove to be the long-sought ubiquitous NDD trigger. We focus on two major NDDs - Alzheimer's disease (AD) and Parkinson's disease (PD), as well as on acquired epilepsy which is an increasingly recognized comorbidity in NDDs. We also discuss available data suggesting the relevance of the proposed mechanisms to other NDDs. We delve into the commonalities among these NDDs in neuroinflammation and NOX involvement to identify potential therapeutic targets and gain a deeper understanding of the underlying causes of NDDs.

Neurodegeneration, a term that refers to the progressive loss of structure and function of neurons, is a feature of many neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). There is no cure or treatment available that can prevent or reverse neurodegenerative conditions. The causes of neurodegeneration in these diseases remain largely unknown; yet, an extremely small proportion of these devastating diseases are associated with genetic mutations in proteins involved in a wide range of cellular pathways and processes. Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA-binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different invitro and invivo experimental models. As such, the investigation of TDP-43 pathomechanisms in various major neurodegenerative diseases is on the rise. Here, after a discussion of stages of TDP-43 proteinopathy during disease progression in various major neurodegenerative diseases, we review previous and most recent studies about the potential pathomechanisms with a particular emphasis on ALS, FTLD, and AD, and discuss the possibility of targeting TDP-43 as a common therapeutic approach to treat neurodegenerative diseases.

Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics

Neurodegenerative diseases (NDDs) are increasing serious menaces to human health in the recent years. Despite exhibiting different clinical phenotypes and selective neuronal loss, there are certain common features in these disorders, suggesting the presence of commonly dysregulated pathways. Identifying causal genes and dysregulated pathways can be helpful in providing effective treatment in these diseases. Interestingly, in spite of the considerable researches on NDDs, to the best of our knowledge, no dysregulated genes and/or pathways were reported in common across all the major NDDs so far. In this study, for the first time, we have applied the three-way interaction model, as an approach to unravel sophisticated gene interactions, to trace switch genes and significant pathways that are involved in six major NDDs. Subsequently, a gene regulatory network was constructed to investigate the regulatory communication of statistically significant triplets. Finally, KEGG pathway enrichment analysis was applied to find possible common pathways. Because of the central role of neuroinflammation and immune system responses in both pathogenic and protective mechanisms in the NDDs, we focused on immune genes in this study. Our results suggest that "cytokine-cytokine receptor interaction" pathway is enriched in all of the studied NDDs, while "osteoclast differentiation" and "natural killer cell mediated cytotoxicity" pathways are enriched in five of the NDDs each. The results of this study indicate that three pathways that include "osteoclast differentiation", "natural killer cell mediated cytotoxicity" and "cytokine-cytokine receptor interaction" are common in five, five and six NDDs, respectively. Additionally, our analysis showed that Rps27a as a switch gene, together with the gene pair {Il-18, Cx3cl1} form a statistically significant and biologically relevant triplet in the major NDDs. More specifically, we suggested that Cx3cl1 might act as a potential upstream regulator of Il-18 in microglia activation, and in turn, might be controlled with Rps27a in triggering NDDs.

Neurodegeneration describes the loss of neuronal structure and function. Numerous neurodegenerative diseases are associated with neurodegeneration. Many are rare and stem from purely genetic causes. However, the prevalence of major neurodegenerative diseases is increasing with improvements in treating major diseases such as cancers and cardiovascular diseases, resulting in an aging population. The neurological consequences of neurodegeneration in patients can have devastating effects on mental and physical functioning. The causes of most cases of prevalent neurodegenerative diseases are unknown. The role of neurotoxicant exposures in neurodegenerative disease has long been suspected, with much effort devoted to identifying causative agents. However, causative factors for a significant number of cases have yet to be identified. In this review, the role of environmental neurotoxicant exposures on neurodegeneration in selected major neurodegenerative diseases is discussed. Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis were chosen because of available data on environmental influences. The special sensitivity the nervous system exhibits to toxicant exposure and unifying mechanisms of neurodegeneration are explored.

Protein aggregate spreading in neurodegenerative diseases: Problems and perspectives

Targeting the epigenome to treat neurodegenerative diseases or delay their onset: a perspective

Becoming increasingly prevalent in recent years, the three major neurodegenerative diseases - Alzheimer’s (AD) Parkinson’s (PD), and Huntington’s (HD) - continue to avoid most attempts at treatment and early diagnosis. Operating under the same pathogenic umbrella of neuronal death, it stands to reason that these, and all other neurodegenerative diseases would share risk factors by virtue of their similar pathologies. The aim of this study is to analyze and compare the molecular signatures of the three neurodegenerative diseases, using a holistic approach, in order to uncover a common signature among them. To achieve this, three gene expression datasets are used, one for each disease. A molecular signature of each of the three neurodegenerative diseases is defined using system biology approaches. The resulting signatures are interrogated for any statistically significant overlap between the diseases at different genomic levels. The results of the overlap analysis point to common malfunctions in various autophagic, apoptotic, and mitophagic pathways. Locating a shared signature of the three diseases opens new avenues for drug repositioning across neurodegenerative diseases, offering novel ways of prevention and treatment and supporting future research toward precision medicine.

Neurodegenerative diseases are incurable and devastating neurological disorders characterized by the progressive loss of the structure and function of neurons in the central nervous system or peripheral nervous system. Mitochondria, organelles found in most eukaryotic cells, are essential for neuronal survival and are involved in a number of neuronal functions. Mitochondrial dysfunction has long been demonstrated as a common prominent early pathological feature of a variety of common neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Mitochondria are highly dynamic organelles that undergo continuous fusion, fission, and transport, the processes of which not only control mitochondrial morphology and number but also regulate mitochondrial function and location. The importance of mitochondrial dynamics in the pathogenesis of neurodegenerative diseases has been increasingly unraveled after the identification of several key fusion and fission regulators such as Drp1, OPA1, and mitofusins. In this review, after a brief discussion of molecular mechanisms regulating mitochondrial fusion, fission, distribution, and trafficking, as well as the important role of mitochondrial dynamics for neuronal function, we review previous and the most recent studies about mitochondrial dynamic abnormalities observed in various major neurodegenerative diseases and discuss the possibility of targeting mitochondrial dynamics as a likely novel therapeutic strategy for neurodegenerative diseases.

Microtubules (MTs) are fundamental polymers composed by α and β tubulin, they provide integrity to neuronal cell and are necessaries in intracellular trafficking and organization. The extension and retraction of MTs occur with the addition or removal of α and β tubulin subunits and the binding with microtubule associated proteins (MAPs) that selectively target specific tubulin regions, manipulating the MT dynamics and function. Altered MT homeostasis can compromise the function of MTs in the structural integrity and axonal transport inside the neuron. Here I review the evidence of MT anomalies in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis and traumatic brain injury and psychiatric disorders, such as depression, schizophrenia, and bipolar disorder. The focus of this review is to point out which can be the impact of MT issues in the major neurodegenerative diseases and discuss which MT abnormalities can lead to psychiatric illnesses.

Recent advances have revealed common pathological changes in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis with related frontotemporal dementia (ALS/FTD). Many of these changes can be linked to alterations in endoplasmic reticulum (ER)-mitochondria signaling, including dysregulation of Ca2+ signaling, autophagy, lipid metabolism, ATP production, axonal transport, ER stress responses and synaptic dysfunction. ER-mitochondria signaling involves specialized regions of ER, called mitochondria-associated membranes (MAMs). Owing to their role in neurodegenerative processes, MAMs have gained attention as they appear to be associated with all the major neurodegenerative diseases. Furthermore, their specific role within neuronal maintenance is being revealed as mutant genes linked to major neurodegenerative diseases have been associated with damage to these specialized contacts. Several studies have now demonstrated that these specialized contacts regulate neuronal health and synaptic transmission, and that MAMs are damaged in patients with neurodegenerative diseases. This Review will focus on the role of MAMs and ER-mitochondria signaling within neurons and how damage of the ER-mitochondria axis leads to a disruption of vital processes causing eventual neurodegeneration.

Dietary Pattern Score, Diet Quality, and Major Neurodegenerative Diseases: A Meta-analysis of Observational Cohort Studies (OR33-07-19)

Occupational exposures to magnetic fields and neurodegenerative disease risks

Functional and structural connectivity measures, as assessed by means of functional and diffusion MRI, are emerging as potential intermediate biomarkers for Alzheimer disease (AD) and other disorders. This Review aims to summarize current evidence that connectivity biomarkers are associated with upstream and downstream disease processes (molecular pathology and clinical symptoms, respectively) in the major neurodegenerative diseases. The vast majority of studies have addressed functional and structural connectivity correlates of clinical phenotypes, confirming the predictable correlation with topography and disease severity in AD and frontotemporal dementia. In neurodegenerative diseases with motor symptoms, structural--but, to date, not functional--connectivity has been consistently found to be associated with clinical phenotype and disease severity. In the latest studies, the focus has moved towards the investigation of connectivity correlates of molecular pathology. Studies in cognitively healthy individuals with brain amyloidosis or genetic risk factors for AD have shown functional connectivity abnormalities in preclinical disease stages that are reminiscent of abnormalities observed in symptomatic AD. This shift in approach is promising, and may aid identification of early disease markers, establish a paradigm for other neurodegenerative disorders, shed light on the molecular neurobiology of connectivity disruption and, ultimately, clarify the pathophysiology of neurodegenerative diseases.

Alkaloids and flavonoids of Solanaceae: Mechanisms of action in neurodegenerative diseases.