Single-gene mutations in mtDNA-associated proteins are unlikely to be the main cause of sporadic Parkinson's disease. Cumulative genetic variation in numerous genes may be important in neurodegeneration and PD risk

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variation ◽  
Mitochondrial Gene ◽  
Single Gene ◽  
Gene Mutations ◽  
Substantia Nigra Pars Compacta ◽  
Mtdna Mutations ◽  
Age Related ◽  
Associated Proteins

More than two decades ago, numerous individuals with mitochondrial abnormalities and Parkinson's disease were reported. Some of these individuals have mtDNA (mtDNA) mutations, which cause instability. Patients who had neurodegeneration in the SNpc showed that mtDNA abnormalities were important in neurodegeneration and PD risk. Similar findings were found in the MitoPark mice as in PD. Single-gene mutations in mtDNA-associated proteins are unlikely to be the main cause of sporadic PD. The mutation in several genes, functioning in concert in intricate functional networks, results in mild to moderate PD symptoms. Single-gene and PD-GWA studies have had little success in uncovering mtDNA risk loci. In this case, mitochondrial biogenesis and compensation processes are associated with the missing compensatory mechanisms in PD. Maintaining a source of wild-type mtDNA helps to fight age-related development of mtDNA abnormalities. PD risk may be enhanced by increasing age-related neuronal loss, if dysregulated or inhibited.Additionally, PD genes, such as PRKN, LRRK2, are multi-taskers. This involves mtDNA participation as well. Some new discoveries connect mtDNA maintenance and mtDNA stress with PRKN/PINK1 PD-mediated inflammation. mtDNA maintenance pathways might potentially be crucial for monogenic PD. How mitochondria can affect monogenic and sporadic kinds of PD is unknown. Continual study only deepens our understanding of the mitochondrial transcriptome. Additionally, mtDNA is known to encode peptides, mRNAs, and small and long noncoding RNAs. These control mitochondrial gene expression, metabolic activity, and stress response. MtDNA mutations impact the nuclear epigenome through creating variations in mitochondrial intermediates that regulate histones. Additionally, mitochondrial DNA polymerases are present. This creates brand-new possibilities for mtDNA replication and repair. We have identified evidence that nDNA that codes for and/or regulates mitochondrial related activities may add to Parkinson's disease (PD) risk. Cumulative genetic variation in numerous genes (including the NRF-1 and NRF-2 pathway) may be important in neurodegeneration and PD risk. It will need more research to figure out which mtDNA gene mutations are responsible for increasing PD risk.The gradual loss of dopaminergic neurons in the substantia nigra pars compacta is one of the defining characteristics of Parkinson's disease (PD) (SNpc). Rigidity, tremor, and bradykinesia are preceded by hallucinations and sleep difficulties as a result of nigrostriatal dopamine depletion. Symptoms vary greatly and their presence and intensity fluctuate over time. Parkinsonism is a catch-all name for a variety of neurological illnesses, including PD, that can cause symptoms that mimic PD. Parkinsonism instances that lack all of the essential symptoms are referred to as parkinsonism instances.

scholarly journals Impact of Aging on the 6-OHDA-Induced Rat Model of Parkinson’s Disease

2020 ◽  
Vol 21 (10) ◽  
pp. 3459 ◽  
Author(s):  
Sandra Barata-Antunes ◽  
Fábio G. Teixeira ◽  
Bárbara Mendes-Pinheiro ◽  
Ana V. Domingues ◽  
Helena Vilaça-Faria ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Welfare ◽  
Neurodegenerative Disorder ◽  
Negative Impact ◽  
Substantia Nigra Pars Compacta ◽  
Nigrostriatal Pathway ◽  
Aged Rats ◽  
Age Related ◽  
The Impact

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. The neurodegeneration leading to incapacitating motor abnormalities mainly occurs in the nigrostriatal pathway due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Several animal models have been developed not only to better understand the mechanisms underlying neurodegeneration but also to test the potential of emerging disease-modifying therapies. However, despite aging being the main risk factor for developing idiopathic PD, most of the studies do not use aged animals. Therefore, this study aimed at assessing the effect of aging in the unilateral 6-hydroxydopamine (6-OHDA)-induced animal model of PD. For this, female young adult and aged rats received a unilateral injection of 6-OHDA into the medial forebrain bundle. Subsequently, the impact of aging on 6-OHDA-induced effects on animal welfare, motor performance, and nigrostriatal integrity were assessed. The results showed that aging had a negative impact on animal welfare after surgery. Furthermore, 6-OHDA-induced impairments on skilled motor function were significantly higher in aged rats when compared with their younger counterparts. Nigrostriatal histological analysis further revealed an increased 6-OHDA-induced dopaminergic cell loss in the SNpc of aged animals when compared to young animals. Overall, our results demonstrate a higher susceptibility of aged animals to 6-OHDA toxic insult.

Protein stability and aggregation in Parkinson's disease

2008 ◽  
Vol 413 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Philip A. Robinson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Clinical Symptoms ◽  
Disease Process ◽  
Substantia Nigra Pars Compacta ◽  
Mitochondrial Activity ◽  
Apparent Paradox ◽  
Lewy Neurites ◽  
Age Related

Parkinson's disease (PD), the second most common age-related neurodegenerative disease, results in abnormalities in motor functioning. Many fundamental questions regarding its aetiology remain unanswered. Pathologically, it is not until 70–80% of the dopaminergic neurons from the substantia nigra pars compacta are lost before clinical symptoms are observed. Thus research into PD is complicated by this apparent paradox in that what appears to be the beginning of the disease at the clinical level is really the end point neurochemically. Consequently, we can only second guess when the disease started and what initiated it. The causation is probably complex, with contributions from both genetic and environmental factors. Intracellular proteinaceous inclusions, Lewy bodies and Lewy neurites, found in surviving dopaminergic neurons, are the key pathological characteristic of PD. Their presence points to an inability within these terminally differentiated cells to deal with aggregating proteins. Recent advances in our knowledge of the underlying disease process have come about from studies on models based on genes associated with rare hereditary forms of PD, and mitochondrial toxins that mimic the behavioural effects of PD. The reason that dopaminergic neurons are particularly sensitive may be due to the additional cellular stress caused by the breakdown of the inherently chemically unstable neurotransmitter, dopamine. In the present review, I discuss the proposal that in sporadic disease, interlinked problems of protein processing and inappropriate mitochondrial activity seed the foundation for age-related increased levels of protein damage, and a reduced ability to deal with the damage, leading to inclusion formation and, ultimately, cell toxicity.

Neurodegenerative disorders and the current state, pathophysiology and management of Parkinson’s disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Rahul ◽  
Yasir Siddique
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
General Concept ◽  
Substantia Nigra Pars Compacta ◽  
Protein Accumulation ◽  
Molecular Pathways ◽  
Environmental Toxicants ◽  
Prognostic Accuracy ◽  
Oligomeric Form ◽  
Associated Proteins

: In last few decades major knowledge has been gained about pathophysiological aspects and molecular pathways behind Parkinson’s disease (PD). Based on neurotoxicological studies and postmortem investigations, now there is a general concept that how environmental toxicants (neurotoxins, pesticides insecticides) and genetic factors (genetic mutations in PD-associated proteins) cause depletion of dopamine from substantia nigra pars compacta region of midbrain and modulate cellular processes leading to pathogenesis of PD. α-Synuclein, a neuronal protein accumulation in oligomeric form, called protofibrils is associated with cellular dysfunction and neuronal death thus possibly contributing to PD propagation. With advances made in identifying loci that contribute for PD, molecular pathways involved in disease pathogenesis are now clear and introducing therapeutic strategy at right time may delay the progression. Biomarkers for PD has helped to monitor PD progression, so personalized therapeutic strategies can be facilitated. In order to further improve PD diagnostic and prognostic accuracy, biomarkersfurther large independent validation is required.

scholarly journals The cell biology of Parkinson’s disease

2021 ◽  
Vol 220 (4) ◽  
Author(s):  
Nikhil Panicker ◽  
Preston Ge ◽  
Valina L. Dawson ◽  
Ted M. Dawson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Signaling Pathways ◽  
Cell Biology ◽  
Neurodegenerative Disorder ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Cellular Functions ◽  
Neuron Death ◽  
Associated Proteins

Parkinson’s disease (PD) is a progressive neurodegenerative disorder resulting from the death of dopamine neurons in the substantia nigra pars compacta. Our understanding of PD biology has been enriched by the identification of genes involved in its rare, inheritable forms, termed PARK genes. These genes encode proteins including α-syn, LRRK2, VPS35, parkin, PINK1, and DJ1, which can cause monogenetic PD when mutated. Investigating the cellular functions of these proteins has been instrumental in identifying signaling pathways that mediate pathology in PD and neuroprotective mechanisms active during homeostatic and pathological conditions. It is now evident that many PD-associated proteins perform multiple functions in PD-associated signaling pathways in neurons. Furthermore, several PARK proteins contribute to non–cell-autonomous mechanisms of neuron death, such as neuroinflammation. A comprehensive understanding of cell-autonomous and non–cell-autonomous pathways involved in PD is essential for developing therapeutics that may slow or halt its progression.

Neuroprotective effect of agmatine (decarboxylated l-arginine) against oxidative stress and neuroinflammation in rotenone model of Parkinson’s disease

2018 ◽  
Vol 38 (2) ◽  
pp. 173-184 ◽  
Author(s):  
EK El-Sayed ◽  
AAE Ahmed ◽  
EM El Morsy ◽  
S Nofal
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Body Weight ◽  
Neuroprotective Effect ◽  
Substantia Nigra Pars Compacta ◽  
Sprague Dawley ◽  
Necrosis Factor Alpha ◽  
Age Related ◽  
Sprague Dawley Rats

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer’s disease, characterized by loss of dopaminergic neurons in substantia nigra pars compacta, accompanied by motor and nonmotor symptoms. The neuropathological hallmarks of PD are well reported, but the etiology of the disease is still undefined; several studies assume that oxidative stress, mitochondrial defects, and neuroinflammation play vital roles in the progress of the disease. The current study was established to investigate the neuroprotective effect of agmatine on a rotenone (ROT)-induced experimental model of PD. Adult male Sprague Dawley rats were subcutaneously injected with ROT at a dose of 2 mg/kg body weight for 35 days. Agmatine was injected intraperitoneally at 50 and 100 mg/kg body weight, 1 h prior to ROT administration. ROT-treated rats that received agmatine showed better performance on beam walking and an elevated number of rears within the cylinder test. In addition, agmatine reduced midbrain malondialdehyde as an indication of lipid peroxidation, pro-inflammatory cytokines including tumor necrosis factor alpha and interleukin-1β, and glial fibrillary acidic protein. Moreover, agmatine was responsible for preventing loss of tyrosine hydroxylase-positive neurons. In conclusion, our study showed that agmatine possesses a dose-dependent neuroprotective effect through its antioxidant and anti-inflammatory activities. These findings need further clinical investigations of agmatine as a promising neuroprotective agent for the future treatment of PD.

scholarly journals Genetic Modifiers of Pathogenic LRRK2 G2019S Neurodegeneration in Drosophila

2018 ◽  
Author(s):  
Sierra Lavoy ◽  
Vinita G. Chittoor-Vinod ◽  
Clement Y. Chow ◽  
Ian Martin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variation ◽  
Genome Wide Association Study ◽  
Neuronal Degeneration ◽  
Pathogenic Mutation ◽  
Genetic Modifiers ◽  
Age Related ◽  
A Genome ◽  
Lrrk2 G2019s

AbstractDisease phenotypes can be highly variable among individuals with the same pathogenic mutation. There is increasing evidence that background genetic variation is a strong driver of disease variability in addition to the influence of environment. To understand the genotype-phenotype relationship that determines the expressivity of a pathogenic mutation, a large number of backgrounds must be studied. This can be efficiently achieved using model organism collections such as the Drosophila Genetic Reference Panel (DGRP). Here, we used the DGRP to assess the variability of locomotor dysfunction in a LRRK2 G2019S Drosophila melanogaster model of Parkinson’s disease. We find substantial variability in the LRRK2 G2019S locomotor phenotype in different DGRP backgrounds. A genome-wide association study for candidate genetic modifiers reveals 177 genes that drive wide phenotypic variation, including 19 top association genes. Genes involved in the outgrowth and regulation of neuronal projections are enriched in these candidate modifiers. RNAi functional testing of the top association and neuronal projection-related genes reveals that pros, pbl, ct and CG33506 significantly modify age-related dopamine neuron loss and associated locomotor dysfunction in the Drosophila LRRK2 G2019S model. These results demonstrate how natural genetic variation can be used as a powerful tool to identify genes that modify disease-related phenotypes. We report novel candidate modifier genes for LRRK2 G2019S that may be used to interrogate the link between LRRK2, neurite regulation and neuronal degeneration in Parkinson’s disease.

scholarly journals Effects of Aging in the Striatum and Substantia Nigra of a Parkinson’s Disease Animal Model

2018 ◽  
Vol 46 (3) ◽  
pp. 348-358 ◽  
Author(s):  
Rodrigo Portes Ureshino ◽  
Angelica Jardim Costa ◽  
Adolfo Garcia Erustes ◽  
Gustavo José da Silva Pereira ◽  
Rita Sinigaglia-Coimbra ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Substantia Nigra Pars Compacta ◽  
Mobility Impairment ◽  
Ultrastructural Alterations ◽  
Age Related ◽  
Effects Of Aging ◽  
Species Production

Aging is a multifactorial process associated with functional deficits, and the brain is more prone to developing chronic degenerative diseases such as Parkinson’s disease. Several groups have tried to correlate the age-related ultrastructural alterations to the neurodegeneration process using in vivo pharmacological models, but due to the limitations of the animal models, particularly in aged animals, the results are difficult to interpret. In this work, we investigated neurodegeneration induced by rotenone, as a pharmacological model of Parkinson’s disease, in both young and aged Wistar rats. We assessed animal mobility, tyrosine hydroxylase staining in the substantia nigra pars compacta (SNpc), and TdT-mediated dUTP-biotin nick end labeling-positive nuclei and reactive oxygen species production in the striatum. Interestingly, the mobility impairment, dopaminergic neuron loss, and elevated number of apoptotic nuclei in the striatum of aged control rats were similar to young rotenone-treated animals. Moreover, we observed many ultrastructural alterations, such as swollen mitochondria in the striatum, and massive lipofuscin deposits in the SNpc of the aged rotenone-treated animals. We conclude that the rotenone model can be employed to explore age-related alterations in the ontogeny that can increase vulnerability in the striatum and SNpc, which may contribute to Parkinson’s disease pathogenesis.

scholarly journals Dual Effects of Human Placenta-Derived Neural Cells on Neuroprotection and the Inhibition of Neuroinflammation in a Rodent Model of Parkinson’s Disease

2018 ◽  
Vol 27 (5) ◽  
pp. 814-830 ◽  
Author(s):  
Han Wool Kim ◽  
Hyun-Seob Lee ◽  
Jun Mo Kang ◽  
Sang-Hun Bae ◽  
Chul Kim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Human Placenta ◽  
Precursor Cells ◽  
Rodent Model ◽  
Neural Precursor Cells ◽  
Substantia Nigra Pars Compacta ◽  
Neural Precursor ◽  
Age Related ◽  
Therapeutic Mechanisms

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease in the elderly and the patients suffer from uncontrolled movement disorders due to loss of dopaminergic (DA) neurons on substantia nigra pars compacta (SNpc). We previously reported that transplantation of human fetal midbrain-derived neural precursor cells restored the functional deficits of a 6-hydroxy dopamine (6-OHDA)-treated rodent model of PD but its low viability and ethical issues still remain to be solved. Albeit immune privilege and neural differentiation potentials suggest mesenchymal stem cells (MSCs) from various tissues including human placenta MSCs (hpMSCs) for an alternative source, our understanding of their therapeutic mechanisms is still limited. To expand our knowledge on the MSC-mediated PD treatment, we here investigated the therapeutic mechanism of hpMSCs and hpMSC-derived neural phenotype cells (hpNPCs) using a PD rat model. Whereas both hpMSCs and hpNPCs protected DA neurons in the SNpc at comparable levels, the hpNPC transplantation into 6-OHDA treated rats exhibited longer lasting recovery in motor deficits than either the saline or the hpMSC treated rats. The injected hpNPCs induced delta-like ligand (DLL)1 and neurotrophic factors, and influenced environments prone to neuroprotection. Compared with hpMSCs, co-cultured hpNPCs more efficiently protected primary neural precursor cells from midbrain against 6-OHDA as well as induced their differentiation into DA neurons. Further experiments with conditioned media from hpNPCs revealed that the secreted factors from hpNPCs modulated immune responses and neural protection. Taken together, both DLL1-mediated contact signals and paracrine factors play critical roles in hpNPC-mediated improvement. First showing here that hpMSCs and their neural derivative hpNPCs were able to restore the PD-associated deficits via dual mechanisms, neuroprotection and immunosuppression, this study expanded our knowledge of therapeutic mechanisms in PD and other age-related diseases.

Gene therapy for Parkinson's disease

2004 ◽  
Vol 6 (5) ◽  
pp. 1-18 ◽  
Author(s):  
Patricia A. Lawlor ◽  
Matthew J. During
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Gene Transfer ◽  
Neurodegenerative Disorder ◽  
Single Gene ◽  
Neuronal Population ◽  
Substantia Nigra Pars Compacta ◽  
Current Standard ◽  
Transfer Strategies

Parkinson's disease (PD) is a debilitating neurodegenerative disorder arising from loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent depletion of striatal dopamine levels, which results in distressing motor symptoms. The current standard pharmacological treatment for PD is direct replacement of dopamine by treatment with its precursor, levodopa (L-dopa). However, this does not significantly alter disease progression and might contribute to the ongoing pathology. Several features of PD make this disease one of the most promising targets for clinical gene therapy of any neurological disease. The confinement of the major pathology to a compact, localised neuronal population and the anatomy of the basal ganglia circuitry mean that global gene transfer is not required and there are well-defined sites for gene transfer. The multifactorial aetiology of idiopathic PD means that it is unlikely any single gene will cure the disease, and as a result at least three separate gene-transfer strategies are currently being pursued: transfer of genes for enzymes involved in dopamine production; transfer of genes for growth factors involved in dopaminergic cell survival and regeneration; and transfer of genes to reset neuronal circuitry by switching cellular phenotype. The merits of these strategies are discussed here, along with remaining hurdles that might impede transfer of gene therapy technology to the clinic as a treatment for PD.

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