Parkinson's disease (PD) is a progressive and incurable neurodegenerative disorder. Although numerous genetic and environmental factors have been linked to the aetiology of PD the underlying ...pathobiology remains poorly understood, hampering the development of improved therapies. Transcriptomics has the potential to reveal significant insights into disease processes. In this review, we focused on published transcriptomics studies on PD with the aim of summarizing studies and identifying common biological pathways. A total of 96 articles were identified as follows: 12 meta‐analyses, 21 re‐analyses of existing data and 63 original studies. Of the 63 original studies, 33 were performed on brain tissue, 26 on blood, three on cerebrospinal fluid and one on skin. In the brain studies, altered pathways identified included those involved in dopamine metabolism, mitochondrial function, oxidative stress, protein degradation, neuroinflammation, vesicular transport and synaptic transmission. Studies on blood samples revealed alterations in pathways involved in immune function, inflammation, RNA processing, protein chaperones, mitochondrial function and programmed cell death. Limitations of these studies include small sample sizes (generally <40 cases/40 controls) and the application of widely varying statistical analysis and parameters. Only eight studies used the RNA‐Seq technique. This review highlights the need for harmonization of transcriptomic approaches and the statistical analyses, and for the data to be deposited into publicly available databases in a standardized format for meta‐analyses. Notably, the concordance of several pathways such as mitochondrial function, protein degradation and inflammation, identified in both blood and brain tissues, suggests that the disease process is systemic and not restricted to neurological tissues.
A review of 96 articles on genome‐wide transcriptomic studies in Parkinson's disease revealed several overlapping and non‐overlapping pathways. The need for harmonization of statistical analyses, and for the data to be deposited into databases in a standardized format for meta‐analyses, is highlighted. Processes such as mitochondrial function, protein degradation and inflammation, identified in both blood and brain tissues, suggest that the disease process is systemic.
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.
The global burden of neurodegenerative disorders has increased substantially over the past 2 decades due to rising rates of population aging. Although neurodegenerative disorders differ in their ...clinical presentation, the underlying pathobiological processes are largely shared. Oxidative stress, among other mechanisms, is strongly implicated in neurodegenerative disorders and aging, and can potentially be targeted by antioxidative agents. Curcumin, a component of turmeric, is a compound that has received considerable attention for its therapeutic properties, and it is considered to be a powerful antioxidant. In this review, we analyzed the evidence for curcumin as an antioxidant in models of neurodegenerative disorders as well as oxido-nitrosative stress. A total of 1451 articles were found from 3 scientific literature databases (PubMed, Scopus, and Web of Science). After all exclusions, a final total of 64 articles were included in this review. The majority of the studies showed that curcumin, or derivatives thereof, were protective against oxidative and/or nitrosative stress in various cellular and animal models. Overall, curcumin protected against lipid and protein oxidation with a reduction in levels of malondialdehyde, and protein carbonyls, thiols and nitrotyrosines. Furthermore, it stimulated the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. In conclusion, curcumin appears to be a promising compound for phytomedicine. However, due to some concerns about its efficacy, further targeted experiments are needed to identify its exact molecular targets and pathways responsible for its antioxidant effects.
•64 relevant articles were found in animal and cellular models of neurodegeneration, aging and oxido-nitrosative stress.•The majority of studies showed curcumin alleviated oxidative stress under a wide range of experimental conditions.•Curcumin inhibited lipid and protein oxidation by suppressing malondialdehyde and protein carbonyls.•Curcumin stimulated the activities of various antioxidant enzymes, including superoxide dismutase and catalase.
Parkinson’s disease (PD) is a movement disorder associated with severe loss of mainly dopaminergic neurons in the substantia nigra. Pathological hallmarks include Lewy bodies, and loss of ...neuromelanin, due to degeneration of neuromelanin-containing dopaminergic neurons. Despite being described over 200 years ago, the etiology of PD remains unknown. Here, we highlight the roles of reactive oxygen species (ROS), iron, alpha synuclein (α-syn) and neuromelanin in a toxic feedback loop culminating in neuronal death and spread of the disease. Dopaminergic neurons are particularly vulnerable due to decreased antioxidant concentration with aging, constant exposure to ROS and presence of neurotoxic compounds (e.g. ortho-quinones). ROS and iron increase each other’s levels, creating a state of oxidative stress. α-Syn aggregation is influenced by ROS and iron but also increases ROS and iron via its induced mitochondrial dysfunction and ferric-reductase activity. Neuromelanin’s binding affinity is affected by increased ROS and iron. Furthermore, during neuronal death, neuromelanin is degraded in the extracellular space, releasing its bound toxins. This cycle of events continues to neighboring neurons in the form of a toxic loop, causing PD pathology. The increase in ROS and iron may be an important target for therapies to disrupt this toxic loop, and therefore diets rich in certain ‘nutraceuticals’ may be beneficial. Turmeric is an attractive candidate, as it is known to have anti-oxidant and iron chelating properties. More studies are needed to test this theory and if validated, this would be a step towards development of lifestyle-based therapeutic modalities to complement existing PD treatments.
Synaptopathies are brain disorders characterized by dysfunctional synapses, which are specialized junctions between neurons that are essential for the transmission of information. Synaptic ...dysfunction can occur due to mutations that alter the structure and function of synaptic components or abnormal expression levels of a synaptic protein. One class of synaptic proteins that are essential to their biology are cell adhesion proteins that connect the pre- and post-synaptic compartments. Neurexins are one type of synaptic cell adhesion molecule that have, recently, gained more pathological interest. Variants in both neurexins and their common binding partners, neuroligins, have been associated with several neuropsychiatric disorders. In this review, we summarize some of the key physiological functions of the neurexin protein family and the protein networks they are involved in. Furthermore, examination of published literature has implicated neurexins in both neuropsychiatric and neurodegenerative disorders. There is a clear link between neurexins and neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia. However, multiple expression studies have also shown changes in neurexin expression in several neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Therefore, this review highlights the potential importance of neurexins in brain disorders and the importance of doing more targeted studies on these genes and proteins.
Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain. Autosomal recessive, early‐onset cases of PD are predominantly caused by mutations in the parkin, PINK1 ...and DJ‐1 genes. Animal and cellular models have verified a direct link between parkin and PINK1, whereby PINK1 phosphorylates and activates parkin at the outer mitochondrial membrane, resulting in removal of dysfunctional mitochondria via mitophagy. Despite the overwhelming evidence for this interaction, few studies have been able to identify a link for DJ‐1 with parkin or PINK1. The aim of this review is to summarise the functions of these three proteins, and to analyse the existing evidence for direct and indirect interactions between them. DJ‐1 is able to rescue the phenotype of PINK1‐knockout Drosophila models, but not of parkin‐knockouts, suggesting that DJ‐1 may act in a parallel pathway to that of the PINK1/parkin pathway. To further elucidate a commonality between these three proteins, bioinformatics analysis established that Miro (RHOT1) interacts with parkin and PINK1, and HSPA4 interacts with all three proteins. Furthermore, 30 transcription factors were found to be common amongst all three proteins, with many of them being involved in transcriptional regulation. Interestingly, expression of these proteins and their associated transcription factors are found to be significantly down‐regulated in PD patients compared to healthy controls. In summary, this review provides insight into common pathways linking three PD‐causing genes and highlights some key questions, the answers to which may provide critical insight into the disease process.
This review summarises the functions and direct/indirect interactions of three proteins involved in the pathogenesis of Parkinson?s disease, namely parkin, PINK1 and DJ‐1. PINK1 and parkin interact via a common pathway, and it is thought that DJ‐1 may act in a parallel pathway to that of PINK1/parkin. Bioinformatics analysis found that Miro (RHOT1) interacts with parkin and PINK1, and HSPA4 interacts with all three proteins. Furthermore, 30 transcription factors were found to be common amongst all three proteins, with many of them being involved in transcriptional regulation.
The Southern African Human Genome Programme is a national initiative that aspires to unlock the unique genetic character of southern African populations for a better understanding of human genetic ...diversity. In this pilot study the Southern African Human Genome Programme characterizes the genomes of 24 individuals (8 Coloured and 16 black southeastern Bantu-speakers) using deep whole-genome sequencing. A total of ~16 million unique variants are identified. Despite the shallow time depth since divergence between the two main southeastern Bantu-speaking groups (Nguni and Sotho-Tswana), principal component analysis and structure analysis reveal significant (p < 10
) differentiation, and F
analysis identifies regions with high divergence. The Coloured individuals show evidence of varying proportions of admixture with Khoesan, Bantu-speakers, Europeans, and populations from the Indian sub-continent. Whole-genome sequencing data reveal extensive genomic diversity, increasing our understanding of the complex and region-specific history of African populations and highlighting its potential impact on biomedical research and genetic susceptibility to disease.
Parkinson's disease (PD) is a neurodegenerative disorder exhibiting Mendelian inheritance in some families. Next-generation sequencing approaches, including whole exome sequencing (WES), have ...revolutionized the field of Mendelian disorders and have identified a number of PD genes. We recruited a South African family with autosomal dominant PD and used WES to identify a possible pathogenic mutation. After filtration and prioritization, we found five potential causative variants in CFAP65, RTF1, NRXN2, TEP1 and CCNF. The variant in NRXN2 was selected for further analysis based on consistent prediction of deleteriousness across computational tools, not being present in unaffected family members, ethnic-matched controls or public databases, and its expression in the substantia nigra. A protein model for NRNX2 was created which provided a three-dimensional (3D) structure that satisfied qualitative mean and global model quality assessment scores. Trajectory analysis showed destabilizing effects of the variant on protein structure, indicated by high flexibility of the LNS-6 domain adopting an extended conformation. We also found that the known substrate N-acetyl-D-glucosamine (NAG) contributed to restoration of the structural stability of mutant NRXN2. If NRXN2 is indeed found to be the causal gene, this could reveal a new mechanism for the pathobiology of PD.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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