Origins and suppression of oscillations in a computational model of Parkinson’s disease

Efficacy of deep brain stimulation (DBS) for motor signs of Parkinson’s disease (PD) depends in part on post-operative programming of stimulus parameters. There is a need for a systematic approach to tuning parameters based on patient physiology. We used a physiologically realistic computational model of the basal ganglia network to investigate the emergence of a 34 Hz oscillation in the PD state and its optimal suppression with DBS. Discrete time transfer functions were fit to post-stimulus time histograms (PSTHs) collected in open-loop, by simulating the pharmacological block of synaptic connections, to describe the behavior of the basal ganglia nuclei. These functions were then connected to create a mean-field model of the closed-loop system, which was analyzed to determine the origin of the emergent 34 Hz pathological oscillation. This analysis determined that the oscillation could emerge from the coupling between the globus pallidus external (GPe) and subthalamic nucleus (STN). When coupled, the two resonate with each other in the PD state but not in the healthy state. By characterizing how this oscillation is affected by subthreshold DBS pulses, we hypothesize that it is possible to predict stimulus frequencies capable of suppressing this oscillation. To characterize the response to the stimulus, we developed a new method for estimating phase response curves (PRCs) from population data. Using the population PRC we were able to predict frequencies that enhance and suppress the 34 Hz pathological oscillation. This provides a systematic approach to tuning DBS frequencies and could enable closed-loop tuning of stimulation parameters.     

Lingo2 variants associated with essential tremor and Parkinson��s disease

LINGO2, a member of LRR gene family, has been linked with both Essential tremor (ET) and Parkinson's disease (PD). However, there is a lack of conclusive evidence regarding the etiologic role of LINGO2 genetic variants. We investigated the association of LINGO2 variants with ET and PD in two independent Asian countries. A total of 1,262 subjects comprising 499 controls, 436 PD patients, and 327 ET patients were included. Eight LINGO2 variants, including four single-nucleotide polymorphisms (SNPs) and four coding variants, were initially analyzed in one Asian population. SNPs that showed positive association were then replicated in the second independent Asian population, and a pooled analysis was carried out. Out of the eight variants, two SNPs (rs7033345 and rs10812774) revealed significant or strong positive trend in the first Asian population, and these were analyzed in the second Asian population. In the pooled analysis, the CC genotype at rs7033345 had a higher risk of developing PD (OR?=?1.67, 95% CI?=?1.18, 2.35, p?=?0.003) and ET (OR?=?1.50, 95% CI?=?1.02, 2.20, p?=?0.04) under a recessive model. The C allele at rs10812774 increased the risk of ET (OR?=?1.56 95% CI?=?1.10, 2.22, p?=?0.01) via a recessive model. The effect size and direction of trend were in the same direction in each of the two populations. Our study demonstrated for the first time that rs7033345 is associated with PD and ET and rs10812774 with ET among Asians, suggesting that LINGO2 might act as a susceptibility gene for both conditions.     

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.     

Identification of rare genetic variants in novel loci associated with Paget’s disease of bone

In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon–intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency <0.05 or absent from dbSNP (NCBI). We sequenced seven genes in 1p13 locus, three genes in 7q33, three genes in 8q22, and five genes in 15q24 locus. We identified 126 rare variants in at least one patient with PDB of whom 55 were located in 1p13 locus, 32 in 7q33, 10 in 8q22 and 29 in 15q24 locus. We located 71 of these 126 rare variants in an intron, 30 in an exon and 9 in an untranslated region. 60 % of these variants were located in functionally relevant gene regions. Among the 12 missense rare variants in PDB, two (rs62620995 in TM7SF4; rs62641691 in CD276) were predicted to be damaging by in silico analysis tools. Rs62620995, which altered a conserved amino acid (p.Leu397Phe) in the TM7SF4 gene, encoding the DC-STAMP protein involved in osteoclastogenesis through RANK signaling pathway, was found to have a marginal association with PDB (p = 0.09). Rs35500845, located in the CTHRC1 gene, which encodes a regulator of collagen matrix deposition, was also associated with PDB in the French-Canadian population (p = 0.046).     

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.     

PARK2 gene variants in Korean patients with Parkinson’s disease

Mutations in PARK2 are considered a common cause of Parkinson’s disease (PD). To assess the frequency of PARK2 mutations in the Korean population, we screened the PARK2 gene in 83 Korean PD patients: two young onset (YO, ≤ 49), 32 middle onset (MO, 50–69) and 49 late onset (LO, ≥ 70). Detection of the point mutations was performed by direct sequencing of the PARK2 exons, and exonic rearrangements were analyzed using multiplex ligation-dependent probe amplification. Five known PARK2 variants were identified in 53 (63.9 %) of the Korean PD patients: two missense mutations (Y267H and M458L) and three polymorphisms (S167N, L272I and V380L). We also found an increased frequency of PARK2 variants in PD patients and a lowered PD age at onset (AAO) in those having two variants, suggesting that the genetic variation in PARK2 gene might be a genetic risk factor of PD in Korean population.     

Inventory of real world data sources in Parkinson’s disease

Background

Real world data have an important role to play in the evaluation of epidemiology and burden of disease; and in assisting health-care decision-makers, especially related to coverage and payment decisions. However, there is currently no overview of the existing longitudinal real world data sources in Parkinson’s disease (PD) in the USA. Such an assessment can be very helpful, to support a future effort to harmonize real world data collection and use the available resources in an optimal way.

Methods

The objective of this comprehensive literature review is to systematically identify and describe the longitudinal, real world data sources in PD in the USA, and to provide a summary of their measurements (categorized into 8 main dimensions: motor and neurological functions, cognition, psychiatry, activities of daily living, sleep, quality of life, autonomic symptoms and other). The literature search was performed using MEDLINE, EMBASE and internet key word search.

Results

Of the 53 data sources identified between May and August 2016, 16 were still ongoing. Current medications (81%) and comorbidities (79%) were frequently collected, in comparison to medical imaging (36%), genetic information (30%), caregiver burden (11%) and healthcare costs (2%). Many different measurements (n =?108) were performed and an interesting variability among used measurements was revealed.

Conclusions

Many longitudinal real world data sources on PD exist. Different types of measurements have been performed over time. To allow comparison and pooling of these multiple data sources, it will be essential to harmonize practices in terms of types of measurements.

     

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.     

Non-synonymous GIGYF2 variants in Parkinson’s disease from two Asian populations

Mutations in the GIGYF2 gene at the PARK11 locus have recently been reported in Parkinson’s disease (PD). However, the pathogenicity of some of these mutations has been debated. We conducted a comprehensive genetic analysis of the entire GIGYF2 gene in a cohort of young onset and familial PD patients, followed up with screening of specific variants in a separate group of PD and healthy controls. A total of 850 study subjects [450 Parkinson’s disease (PD) patients and 400 controls] from two Asian countries were included. Our analysis revealed 17 variants distributed across the entire GIGYF2 gene. Ten of these were novel variants out of which eight were non-synonymous (all heterozygous). Out of these eight, half were novel polymorphic variants (0.2–2%) whereas four were novel non-synonymous variants which were not detected in healthy controls. The seven PD patients with non-synonymous variants had a mean age and age at onset of 55.3 and 50.9 years. All had typical features of PD and only one had a positive family history. The collective frequency of these non-synonymous variants was higher in PD compared to controls (1.6 vs. 0%, P = 0.016, relative risk 1.9, 95% CI 1.2, 1.9). None of the previously reported pathogenic mutations in Italian and French patients were present in our cohort. Our data suggest that GIGYF2 is unlikely to play a major role in our Asian populations. Rare non-synonymous variants appeared to be enriched in our PD patients compared to healthy controls. However, in vivo functional studies and segregation analysis in large pedigrees will be needed to determine if these single heterozygous variants represent rare mutations, risk alleles or benign polymorphisms.     

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.     

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.

     

Drosophila melanogaster as a model organism for Alzheimer’s disease

Drosophila melanogaster provides an important resource for in vivo modifier screens of neurodegenerative diseases. To study the underlying pathogenesis of Alzheimer’s disease, fly models that address Tau or amyloid toxicity have been developed. Overexpression of human wild-type or mutant Tau causes age-dependent neurodegeneration, axonal transport defects and early death. Large-scale screens utilizing a neurodegenerative phenotype induced by eye-specific overexpression of human Tau have identified several kinases and phosphatases, apoptotic regulators and cytoskeleton proteins as determinants of Tau toxicity in vivo. The APP ortholog of Drosophila (dAPPl) shares the characteristic domains with vertebrate APP family members, but does not contain the human Aβ42 domain. To circumvent this drawback, researches have developed strategies by either direct secretion of human Aβ42 or triple transgenic flies expressing human APP, β-secretase and Drosophila γ-secretase presenilin (dPsn). Here, we provide a brief overview of how fly models of AD have contributed to our knowledge of the pathomechanisms of disease.     

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.     

Environmental toxins and α-synuclein in Parkinson’s disease

In recent years, environmental influences have been thought to play an important role in Parkinson’s disease (PD). Evidence from epidemiological investigations suggests that environmental factors might take part in the disease process. Intriguingly, most of environmental toxins share the common mechanism of causing mitochondria dysfunction by inhibiting complex I and promoting α-synuclein aggregation, a key factor in PD. Therefore, understanding the mechanism of interactions between α-synuclein and environmental factors could lead to new therapeutic approaches to PD.     

The effects of pergolide on memory and oxidative stress in a rat model of Parkinson’s disease

One of the most widely used animal models of Parkinson’s disease (PD) involves injecting 6-hydroxydopamine (6-OHDA) directly into the substantia nigra (SN). Some recent reports speculated that dopaminergic drugs may exert brain antioxidant activity, which could explain some of their protective actions. In this way, the aim of the present study was to examine the effects of low-dose pergolide on memory deficits and brain oxidative stress in a 6-OHDA-induced rat model of PD. Right-unilateral lesions of the SN were produced with 6-OHDA. Two weeks after neurosurgery, pergolide (0.3 mg/kg/day) was injected intraperitoneally in the 6-OHDA + pergolide and sham-operated + pergolide groups, while sham-operated and 6-OHDA alone groups received saline. Radial-8-arm maze and Y-maze were used for memory assessment. We also determined some enzymatic antioxidant defenses like superoxide dismutase or glutathione peroxidase and a lipid peroxidation marker [malondialdehyde (MDA)], from the temporal lobe. A reduced number of working/reference memory errors was observed in 6-OHDA + pergolide group, compared to sham-operated rats. Additionally, post hoc analysis showed significant differences between 6-OHDA and 6-OHDA + pergolide groups in both Y-maze and radial-arm-maze tasks. We also noted a significant decrease of MDA level in the 6-OHDA + pergolide group, compared to sham-operated rats. Significant correlations were also found between behavioral parameters and MDA levels. Our data suggest that pergolide facilitates spatial memory and improves brain oxidative balance, after a 6-OHDA-induced model of PD. This could be useful for further investigations and clinical applications of pergolide.     

NADPH oxidases in Parkinson’s disease: a systematic review

Parkinson’s disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, is thought to play an important role in dopaminergic neurotoxicity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are multi-subunit enzymatic complexes that generate reactive oxygen species as their primary function. Increased immunoreactivities for the NADPH oxidases catalytic subunits Nox1, Nox2 and Nox4 have been reported in the brain of PD patients. Furthermore, knockout or genetic inactivation of NADPH oxidases exert a neuroprotective effect and reduce detrimental aspects of pathology in experimental models of the disease. However, the connections between NADPH oxidases and the biological processes believed to contribute to neuronal death are not well known. This review provides a comprehensive summary of our current understanding about expression and physiological function of NADPH oxidases in neurons, microglia and astrocytes and their pathophysiological roles in PD. It summarizes the findings supporting the role of both microglial and neuronal NADPH oxidases in cellular disturbances associated with PD such as neuroinflammation, alpha-synuclein accumulation, mitochondrial and synaptic dysfunction or disruption of the autophagy-lysosome system. Furthermore, this review highlights different steps that are essential for NADPH oxidases enzymatic activity and pinpoints major obstacles to overcome for the development of effective NADPH oxidases inhibitors for PD.