Mechanistic aspects of Parkinson’s disease: α-synuclein and the biomembrane

A key feature in Parkinson’s disease is the deposition of Lewy bodies. The major protein component of these intracellular deposits is the 140-amino acid protein α-synuclein that is widely distributed throughout the brain. α-synuclein was identified in presynaptic terminals and in synaptosomal preparations. The protein is remarkable for its structural variability. It is almost unstructured as a monomer in aqueous solution. Self-aggregation leads to a variety of β-structures, while membrane association may result in the formation of an amphipathic helical structure. The present article strives to give an overview of what is currently known on the interaction of α-synuclein with lipid membranes, including synthetic lipid bilayers, membraneous cell fractions, synaptic vesicles and intact cells. Manifestations of a functional relevance of the α-synuclein–lipid interaction will be discussed and the potential pathogenicity of oligomeric α-synuclein aggregates will be briefly reviewed.     

Parkin-associated Parkinson’s disease

Mutations in the PARK2 gene coding for parkin cause autosomal recessive juvenile parkinsonism (AR-JP), a familial form of Parkinsons disease (PD). Parkin functions as an E3 ubiquitin ligase, and loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of AR-JP. Recently, the spectrum of genetic, clinical, and pathological findings on AR-JP has been significantly expanded. Moreover, a considerable number of parkin interactors and/or substrates have been identified and characterized, and animal models of parkin deficiency have been generated. In this review, we provide an overview of the most relevant findings and discuss their implications for the pathogenesis of AR-JP and sporadic PD.     

Glutamate and Parkinson’s disease

Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson’s disease (PD). The substantia nigra pars compacta—the area where the primary pathological lesion is located—is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neuro-degenerative disorder.     

Tackling neurodegenerative diseases: animal models of Alzheimer’s disease and Parkinson’s disease

Our ageing society is confronted with a dramatic increase in incidence of age-related neurodegenerative diseases; biomedical research leading to novel therapeutic strategies is crucial to address this problem. Animal models of neurodegenerative conditions are invaluable in improving our understanding of the molecular basis of pathology, potentially revealing novel targets for intervention. Here, we review transgenic animal models of Alzheimer’s and Parkinson’s disease reported in mice, zebrafish, Caenorhabditis elegans and Drosophila melanogaster. This information will enable researchers to compare different animal models targeting disease-associated molecules by genomic engineering and to facilitate the development of novel animal models for any particular study, depending on the ultimate research goals.     

Calcium signaling in Parkinson’s disease

Calcium (Ca²⁺) is an almost universal second messenger that regulates important activities of all eukaryotic cells. It is of critical importance to neurons, which have developed extensive and intricate pathways to couple the Ca²⁺ signal to their biochemical machinery. In particular, Ca²⁺ participates in the transmission of the depolarizing signal and contributes to synaptic activity. During aging and in neurodegenerative disease processes, the ability of neurons to maintain an adequate energy level can be compromised, thus impacting on Ca²⁺ homeostasis. In Parkinson’s disease (PD), many signs of neurodegeneration result from compromised mitochondrial function attributable to specific effects of toxins on the mitochondrial respiratory chain and/or to genetic mutations. Despite these effects being present in almost all cell types, a distinguishing feature of PD is the extreme selectivity of cell loss, which is restricted to the dopaminergic neurons in the ventral portion of the substantia nigra pars compacta. Many hypotheses have been proposed to explain such selectivity, but only recently it has been convincingly shown that the innate autonomous activity of these neurons, which is sustained by their specific Cav1.3 L-type channel pore-forming subunit, is responsible for the generation of basal metabolic stress that, under physiological conditions, is compensated by mitochondrial buffering. However, when mitochondria function becomes even partially compromised (because of aging, exposure to environmental factors or genetic mutations), the metabolic stress overwhelms the protective mechanisms, and the process of neurodegeneration is engaged. The characteristics of Ca²⁺ handling in neurons of the substantia nigra pars compacta and the possible involvement of PD-related proteins in the control of Ca²⁺ homeostasis will be discussed in this review.     

Mitochondrial DNA polymorphisms as risk factors for Parkinson’s disease and Parkinson’s disease dementia

The activity of complex I of the mitochondrial respiratory chain has been found to be decreased in patients with Parkinsons disease (PD), but no mutations have been identified in genes encoding complex I subunits. Recent studies have suggested that polymorphisms in mitochondrial DNA (mtDNA)-encoded complex I genes (MTND) modify susceptibility to PD. We hypothesize that the risk of PD is conveyed by the total number of nonsynonymous substitutions in the MTND genes in various mtDNA lineages rather than by single mutations. To test this possibility, we determined the number of nonsynonymous substitutions of the seven MTND genes from 183 Finns. The differences in the total number of nonsynonymous substitutions and the nonsynonymous to synonymous substitution rate ratio (K_a/K_s) of MTND genes between the European mtDNA haplogroup clusters (HV, JT, KU, IWX) were analysed by using a statistical approach. Patients with PD (n=238) underwent clinical examination together with mtDNA haplogroup analysis and the clinical features between patient groups defined by the number of nonsynonymous substitutions were compared. Our analysis revealed that the haplogroup clusters HV and KU had a lower average number of amino acid replacements and a lower K_a/K_s ratio in the MTND genes than clusters JT and IWX. Supercluster JTIWX with the highest number of amino acid replacements was more frequent among PD patients and even more frequent among patients with PD who developed dementia. Our results suggest that a relative excess of nonsynonymous mutations in MTND genes in supercluster JTWIX is associated with an increased risk of PD and the disease progression to dementia.     

Neuronal pathology in Parkinson’s disease

Parkinsons disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra leading to the major clinical and pharmacological abnormalities of PD. In order to establish causal or protective treatments for PD, it is necessary to identify the cascade of deleterious events that lead to the dysfunction and death of dopaminergic neurons. Based on genetic, neuropathological, and biochemical data in patients and experimental animal models, dysfunction of the ubiquitin-proteasome pathway, protein aggregation, mitochondrial dysfunction, oxidative stress, activation of the c-Jun N-terminal kinase pathway, and inflammation have all been identified as important pathways leading to excitotoxic and apoptotic death of dopaminergic neurons. Toxin-based and genetically engineered animal models allow (1) the study of the significance of these aspects and their interaction with each other and (2) the development of causal treatments to stop disease progression.     

Succinate dehydrogenase in Parkinson’s disease

Background

The prevalence of neurodegenerative disorders such as Parkinson’s disease (PD) is increased by age. Alleviation of their symptoms and protection of normal neurons against degeneration are the main aspects of the researches to establish novel therapeutic strategies. Many studies have shown that mitochondria as the most important organelles in the brain which show impairment in PD models. Succinate dehydrogenase (SDH) as a component of the oxidative phosphorylation system in mitochondria connects Krebs cycle to the electron transport chain. Dysfunction or inhibition of the SDH can trigger mitochondrial impairment and disruption in ATP generation. Excessive in lipid synthesis and induction of the excitotoxicity as inducers in PD are controlled by SDH activity directly and indirectly. On the other hand, mutation in subunits of the SDH correlates with the onset of neurodegenerative disorders. Therefore, SDH could behave as one of the main regulators in neuroprotection.

Objective

In this review we will consider contribution of the SDH and its related mechanisms in PD.

Methods

Pubmed search engine was used to find published studies from 1977 to 2016. “Succinate dehydrogenase”, “lipid and brain”, “mitochondria and Parkinson’s disease” were the main keywords for searching in the engine.

Results

Wide ranges of studies (59 articles) in neurodegenerative disorders especially Parkinson’s disease like genetics of the Parkinson’s disease, effects of the mutant SDH on cell activity and physiology and lipid alteration in neurodegenerative disorders have been used in this review.

Conclusion

Mitochondria as key organelles in the energy generation plays crucial roles in PD. ETC complex in this organelle consists four complexes which alteration in their activities cause ROS generation and ATP depletion. Most of complexes are encoded by mtDNA while complex II is the only part of the ETC which is encoded by nuclear genome. So, focusing on the SDH and related pathways which have important role in neuronal survival and SDH has a potential to further studies as a novel neuroprotective agent.

     

Mitochondrial dysfunction in Parkinson’s disease

The review highlights mitochondrial structural and functional abnormalities in Parkinson’s disease and experimental animal models of this pathology. Special attention is paid to the inactivation of mitochondrial enzymes, mutations in mitochondrial and nuclear DNA, and genomic and proteomic studies of mitochondrial proteins in Parkinson’s disease and experimental parkinsonism in animals.     

Gene therapy in Parkinson’s disease

Gene therapy in Parkinsons disease appears to be at the brink of the clinical study phase. Future gene therapy protocols will be based on a substantial amount of preclinical data regarding the use of ex vivo and in vivo genetic modifications with the help of viral or non-viral vectors. To date, the supplementation of neurotrophic factors and substitution for the dopaminergic deficit have formed the focus of trials to achieve relief in animal models of Parkinsons disease. Newer approaches include attempts to influence detrimental cell signalling pathways and to inhibit overactive basal ganglia structures. Nevertheless, current models of Parkinsons disease do not mirror all aspects of the human disease, and important issues with respect to long-term protein expression, choice of target structures and transgenes and safety remain to be solved. Here, we thoroughly review available animal data of gene transfer in models of Parkinsons disease.     

Molecular genetics of Parkinson’s disease

The current views on the role of genetic factors in the pathogenesis of Parkinson’s disease are considered. The review is focused on monogenic forms of the disease, for which 11 loci are mapped and seven genes whose mutations cause the disease are identified. In addition, a number of candidate genes for sporadic Parkinson’s disease are described. The further development of studying genetic bases of Parkinson’s disease will follow two main directions: in-depth analysis of genes related to the monogenic form of the disease and more large-scale associative investigation of candidate genes for the sporadic form of Parkinson’s disease.     

Chasing genes in Alzheimer’s and Parkinson’s disease

Alzheimers disease (AD), the most common type of dementia, and Parkinsons disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on special isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of gene hunting have evolved during the last few years and the significance of finding genes such as the presenilins, -synuclein, parkin and DJ-1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.     

Parkinson’s disease and enhanced inflammatory response

Parkinson’s disease (PD) is the first and second most prevalent motor and neurodegenerative disease, respectively. The clinical symptoms of PD result from a loss of midbrain dopaminergic (DA) neurons. However, the molecular cause of DA neuron loss remains elusive. Mounting evidence implicates enhanced inflammatory response in the development and progression of PD pathology. This review examines current research connecting PD and inflammatory response.     

Exploring gene-environment interactions in Parkinson’s disease

The objective of this study was to explore combined effects of four candidate susceptibility genes and two exposures on Parkinson’s disease (PD) risk; namely, α-synuclein (SNCA) promoter polymorphism REP1, microtubule-associated protein tau (MAPT) H1/H2 haplotypes, apolipoprotein E (APOE) ε2/ε3/ε4 polymorphism, ubiquitin carboxy-terminal esterase L1 (UCHL1) S18Y variant, cigarette smoking and caffeinated coffee consumption. 932 PD patients and 664 control subjects from the NeuroGenetics Research Consortium, with complete data on all six factors, were studied. Uniform protocols were used for diagnosis, recruitment, data collection and genotyping. A logistic regression model which included gene-exposure interactions was applied. Likelihood ratio tests (LRTs) were used for significance testing and Bayesian inference was used to estimate odds ratios (ORs). MAPT (P = 0.007), SNCA REP1 (P = 0.012), smoking (P = 0.001), and coffee (P = 0.011) were associated with PD risk. Two novel interactions were detected: APOE with coffee (P = 0.005), and REP1 with smoking (P = 0.021). While the individual main effects were modest, each yielding OR < 1.6, the effects were cumulative, with some combinations reaching OR = 12.6 (95% CI: 5.9–26.8). This study provides evidence for the long-held notion that PD risk is modulated by cumulative and interactive effects of genes and exposures. Furthermore, the study demonstrates that while interaction studies are useful for exploring risk relationships that might otherwise go undetected, results should be interpreted with caution because of the inherent loss of power due to multiple testing. The novel findings of this study that warrant replication are the evidence for interaction of coffee with APOE, and of smoking with REP1 on PD risk. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Prevention of progression in Parkinson’s disease

Environmental influences affecting genetically susceptible individuals seem to contribute significantly to the development of Parkinson’s disease (PD). Xenobiotic exposure including transitional metal deposition into vulnerable CNS regions appears to interact with PD genes. Such exposure together with mitochondrial dysfunction evokes a destructive cascade of biochemical events, including oxidative stress and degeneration of the sensitive dopamine (DA) production system in the basal ganglia. Recent research indicates that the substantia nigra degeneration can be decelerated by treatment with iron binding compounds such as deferiprone. Interestingly compounds known to decrease PD risk including caffeine, niacin, nicotine and salbutamol also possess iron binding properties. Adequate function of antioxidative mechanisms in the vulnerable brain cells can be restored by acetylcysteine supplementation to normalize intracellular glutathione activity. Other preventive measures to reduce deterioration of dopaminergic neurons may involve life-style changes such as intake of natural antioxidants and physical exercise. Further research is recommended to identify therapeutic targets of the proposed interventions, in particular protection of the DA biosynthesis by oxygen radical scavengers and iron binding agents.     

MicroRNAs: Possible role in pathogenesis of Parkinson’s disease

Parkinson’s disease is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons from the substantia nigra pars compacta of human brain. However, causes and mechanisms of the progression of the disease are not yet fully clarified. To date, investigation of the role of miRNAs in norm and pathology is one of the most intriguing and actively developing areas in molecular biology. MiRNAs regulate expression of a variety of genes and can be implicated in pathogenesis of various diseases. Possible role of miRNAs in pathogenesis of Parkinson’s disease is discussed in this review.