Mechanisms Implicated in Parkinson Disease from Genetic Perspective

Popescu, Cyprian

doi:10.21767/2471-299x.1000028

Cited by 8 publications

(6 citation statements)

References 217 publications

(254 reference statements)

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“…People affected by PD may show a different phenotype, suggesting different genetic alterations among the causes of PD onset. Furthermore, specific genes involved in PD pathogenesis may indicate the type of development and the severity of the clinical symptomatology [12]. Genetic and environmental factors can modify the biology and the physiology of several biological processes; however, such risk factors seem to be differently able to influence PD severity [13].…”

Section: Factors Impacting Pd Onset and Severitymentioning

confidence: 99%

Human Periapical Cyst-Derived Stem Cells Can Be A Smart “Lab-on-A-Cell” to Investigate Neurodegenerative Diseases and the Related Alteration of the Exosomes’ Content

Tatullo

Codispoti²,

Spagnuolo

et al. 2019

Brain Sciences

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Promising researches have demonstrated that the alteration of biological rhythms may be consistently linked to neurodegenerative pathologies. Parkinson’s disease (PD) has a multifactorial pathogenesis, involving both genetic and environmental and/or molecular co-factors. Generally, heterogeneous alterations in circadian rhythm (CR) are a typical finding in degenerative processes, such as cell aging and death. Although numerous genetic phenotypes have been discovered in the most common forms of PD, it seems that severe deficiencies in synaptic transmission and high vesicular recycling are frequently found in PD patients. Neuron-to-neuron interactions are often ensured by exosomes, a specific type of extracellular vesicle (EV). Neuron-derived exosomes may carry several active compounds, including miRNAs: Several studies have found that circulating miRNAs are closely associated with an atypical oscillation of circadian rhythm genes, and they are also involved in the regulation of clock genes, in animal models. In this context, a careful analysis of neural-differentiated Mesenchymal Stem Cells (MSCs) and the molecular and genetic characterization of their exosome content, both in healthy cells and in PD-induced cells, could be a strategic field of investigation for early diagnosis and better treatment of PD and similar neurodegenerative pathologies. A novel MSC population, called human periapical cyst–mesenchymal stem cells (hPCy–MSCs), has demonstrated that it naively expresswa the main neuronal markers, and may differentiate towards functional neurons. Therefore, hPCy–MSCs can be considered of particular interest for testing of in vitro strategies to treat neurological diseases. On the other hand, the limitations of using stem cells is an issue that leads researchers to perform experimental studies on the exosomes released by MCSs. Human periapical cyst-derived mesenkymal stem cells can be a smart “lab-on-a-cell” to investigate neurodegenerative diseases and the related exosomes’ content alteration.

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Section: Factors Impacting Pd Onset and Severitymentioning

confidence: 99%

Human Periapical Cyst-Derived Stem Cells Can Be A Smart “Lab-on-A-Cell” to Investigate Neurodegenerative Diseases and the Related Alteration of the Exosomes’ Content

Tatullo

Codispoti²,

Spagnuolo

et al. 2019

Brain Sciences

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“…Since α‐synuclein was first linked with familial PD, studies have identified several mutations in α‐synuclein, including the duplication and triplication of the α‐synuclein gene (Chart ier‐Harlin et al, 2004; Fuchs et al, 2007; Kruger et al, 1998; Polymeropoulos et al., 1997; Zarranz et al, 2004) and the point mutations A53T and A30P (Polymeropoulos et al., 1997; Xiong et al., 2009). Mutations in α‐synuclein usually lead to PD around 45–46 years of age, and are autosomal dominant (Popescu, 2016).…”

Section: Genetic Evidence To Support Mitochondria As Central To Pd Pa...mentioning

confidence: 99%

The multi‐faceted role of mitochondria in the pathology of Parkinson’s disease

Trinh

Israwi

Arathoon

et al. 2020

Journal of Neurochemistry

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Mitochondria are essential for neuronal function. They produce ATP to meet energy demands, regulate homeostasis of ion levels such as calcium and regulate reactive oxygen species that cause oxidative cellular stress. Mitochondria have also been shown to regulate protein synthesis within themselves, as well as within the nucleus, and also influence synaptic plasticity. These roles are especially important for neurons, which have higher energy demands and greater susceptibility to stress. Dysfunction of mitochondria has been associated with several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, Glaucoma and Amyotrophic Lateral Sclerosis. The focus of this review is on how and why mitochondrial function is linked to the pathology of Parkinson's disease (PD). Many of the PD‐linked genetic mutations which have been identified result in dysfunctional mitochondria, through a wide‐spread number of mechanisms. In this review, we describe how susceptible neurons are predisposed to be vulnerable to the toxic events that occur during the neurodegenerative process of PD, and how mitochondria are central to these pathways. We also discuss ways in which proteins linked with familial PD control mitochondrial function, both physiologically and pathologically, along with their implications in genome‐wide association studies and risk assessment. Finally, we review potential strategies for disease modification through mitochondrial enhancement. Ultimately, agents capable of both improving and/or restoring mitochondrial function, either alone, or in conjunction with other disease‐modifying agents may halt or slow the progression of neurodegeneration in Parkinson's disease.

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“…Most of the studies on the established PD genes or genes associated with PD including SNCA, LRRK2, PRKN, PINK1, PARK7, ATP13A2 and GBA, have been performed in European, North American, North African Arab or Asian populations [9,13,14]. In general, limited studies exist on the genetics of PD in the Black African populations [15].…”

Section: Introductionmentioning

confidence: 99%

Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson’s disease in Black South African and Nigerian patients

et al. 2020

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Background: The prevalence of Parkinson's disease (PD) is increasing in sub-Saharan Africa, but little is known about the genetics of PD in these populations. Due to their unique ancestry and diversity, sub-Saharan African populations have the potential to reveal novel insights into the pathobiology of PD. In this study, we aimed to characterise the genetic variation in known and novel PD genes in a group of Black South African and Nigerian patients. Methods: We recruited 33 Black South African and 14 Nigerian PD patients, and screened them for sequence variants in 751 genes using an Ion AmpliSeq™ Neurological Research panel. We used bcftools to filter variants and annovar software for the annotation. Rare variants were prioritised using MetaLR and MetaSVM prediction scores. The effect of a variant on ATP13A2's protein structure was investigated by molecular modelling. Results: We identified 14,655 rare variants with a minor allele frequency ≤ 0.01, which included 2448 missense variants. Notably, no common pathogenic mutations were identified in these patients. Also, none of the known PD-associated mutations were found highlighting the need for more studies in African populations. Altogether, 54 rare variants in 42 genes were considered deleterious and were prioritized, based on MetaLR and MetaSVM scores, for follow-up studies. Protein modelling showed that the S1004R variant in ATP13A2 possibly alters the conformation of the protein. Conclusions: We identified several rare variants predicted to be deleterious in sub-Saharan Africa PD patients; however, further studies are required to determine the biological effects of these variants and their possible role in PD. Studies such as these are important to elucidate the genetic aetiology of this disorder in patients of African ancestry.

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Mechanisms Implicated in Parkinson Disease from Genetic Perspective

Cited by 8 publications

References 217 publications

Human Periapical Cyst-Derived Stem Cells Can Be A Smart “Lab-on-A-Cell” to Investigate Neurodegenerative Diseases and the Related Alteration of the Exosomes’ Content

Human Periapical Cyst-Derived Stem Cells Can Be A Smart “Lab-on-A-Cell” to Investigate Neurodegenerative Diseases and the Related Alteration of the Exosomes’ Content

The multi‐faceted role of mitochondria in the pathology of Parkinson’s disease

Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson’s disease in Black South African and Nigerian patients

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