An imbalance of netrin-1 and DCC during nigral degeneration in experimental models and patients with Parkinson's disease

Aims

Multiple guidance cues, such as netrin-1 (NTN-1)/deleted in colorectal carcinoma (DCC), control the guidance of axons and help establish functional neural circuits during development. However, the function of these guidance molecules during the neurodegenerative process is unclear.

Methods

To access the alterations of NTN-1 and DCC during the onset and progression of PD, we first established two subacute and one chronic PD model. Then, we investigated the relationship between the NTN-1/DCC pathway and cell death in SH-SY5Y cells. Finally, we conducted correlation studies between plasma NTN-1 and parkinsonian symptoms in patients to understand how this pathway contributes to PD.

Results

We found that the imbalance of NTN-1 and DCC was a common feature of nigral DA neuron injury in PD mouse models. We investigated that MPP+ inhibited NTN-1 expression and increased DCC expression in a concentration- and time-dependent manner. We further discovered a significant decrease in plasma NTN-1 levels and a positive correlation with UPDRS scores in PD patients.

Conclusion

Our findings confirmed the imbalance of NTN-1/DCC signaling during nigral degeneration in experimental PD models and found for the first time a correlation of plasma NTN-1 with PD symptoms in patients.     

Dopamine signals and physiological origin of cognitive dysfunction in Parkinson's disease

The pathological hallmark of Parkinson's disease (PD) is the degeneration of midbrain dopamine neurons. Cognitive dysfunction is a feature of PD patients even at the early stages of the disease. Electrophysiological studies on dopamine neurons in awake animals provide contradictory accounts of the role of dopamine. These studies have established that dopamine neurons convey a unique signal associated with rewards rather than cognitive functions. Emphasizing their role in reward processing leads to difficulty in developing hypothesis as to how cognitive impairments in PD are associated with the degeneration of dopamine circuitry. A hint to resolve this contradiction came from recent electrophysiological studies reporting that dopamine neurons transmit more diverse signals than previously thought. These studies suggest that dopamine neurons are divided into at least two functional subgroups, one signaling “motivational value” and the other signaling “salience.” The former subgroup fits well with the conventional reward theory, whereas the latter subgroup has been shown to transmit signals related to salient but non‐rewarding experiences such as aversive stimulations and cognitively demanding situations. This article reviews recent advances in understanding the non‐reward functions of dopamine, and then discusses the possibility that cognitive dysfunction in PD is at least partially caused by the degeneration of the dopamine neuron subgroup signaling the salience of events in the environment. 2015 International Parkinson and Movement Disorder Society     

Prevalence and determinants of depression in Mexican patients with Parkinson's disease

Objective

To assess the prevalence and associated factors of depression in a Mexican Parkinson's disease (PD) population.

Background

Depressive symptoms are frequent in PD and have been recognized as a major determinant of quality of life. Only two previous studies have partially addressed depression in Mexican PD patients.

Methods

One hundred forty-seven non-demented PD patients were recruited at the movement disorder specialist clinic at the National Institute of Neurology and Neurosurgery, Mexico City. The following sociodemographic variables were collected: gender, age, age at onset, disease duration and disease severity in terms of Hoehn and Yahr stage. PDQ-8, NMSQuest and Beck Depression Inventory (BDI) were applied to all participants.

Results

One hundred forty-seven patients were included (49.7% female). The mean age of the sample was 62.1 ± 11.7 years, the mean age at diagnosis was 55.8 ± 12.3 and the mean duration of the disease was 6.3 ± 5 years. A total of 49 (33.3%) patients were diagnosed with current depression. Depressed patients also scored higher in the NMSQuest even when depression/anxiety items were excluded. Differences were found in gender, UPDRS III score and HY stage, but after the logistic regression analysis was performed only the NMSQuest score and low education remained as statistically significant factors for depression in Mexican PD patients.

Conclusions

Depression prevalence in PD Mexican patients is similar to other international reports. The main associated factor was the presence of non-motor symptoms.     

The emerging role of Rab GTPases in the pathogenesis of Parkinson's disease

The identification of pathogenic mutations in Ras analog in brain 39B (RAB39B) and Ras analog in brain 32 (RAB32) that cause Parkinson's disease (PD) has highlighted the emerging role of protein trafficking in disease pathogenesis. Ras analog in brain (Rab) Guanosine triphosphatase (GTPase) function as master regulators of membrane trafficking, including vesicle formation, movement along cytoskeletal networks, and membrane fusion. Recent studies have linked Rab GTPases with α‐synuclein, Leucine‐rich repeat kinase 2, and Vacuolar protein sorting 35, 3 key proteins in PD pathogenesis. In this review, we discuss the various RAB GTPases associated with PD, current progress in the research, and potential future directions. Investigations into the function of RAB GTPases will likely provide significant insight into the etiology of PD and identify novel therapeutic targets for a currently incurable disease. © 2018 International Parkinson and Movement Disorder Society     

Age-related influences on the clinical characteristics of new-onset hallucinations in Parkinson's disease patients.

The objective of this study was to determine the demographic influences on the sensory characteristics (pure visual vs. nonvisual or mixed visual/nonvisual) of new-onset hallucinations in Parkinson's disease (PD). We utilized 6-year longitudinal interview data from 60 PD patients who had never hallucinated at baseline and reinterviewed them at 6, 18, 48, and 72 months to assess the presence and type of hallucination that developed as the first form of hallucination. We analyzed data by Generalized Estimating Equations methods and by nonparametric tests. Over 6 years, 37 of 60 patients developed hallucinations, and the first hallucinations were pure visual in 18, pure nonvisual in 9, and mixed visual/nonvisual in 10. At the time of first onset of hallucinations, patients whose hallucinations were nonvisual or mixed were significantly older than those with purely visual hallucinations (mean age, 69.8+/-8.3 vs. 61.9+/-10.6; P=0.031). PD duration in the two groups, however, was statistically comparable (9.6+/-4.4 vs. 12.9+/-8.6 years). Though classically described as visual, hallucinations in PD frequently involve other sensory modalities. Age-related disinhibition may facilitate wider cortical activation in PD and potentiate aberrant signaling that invokes other types of hallucinations besides the classic visual forms.     

Incidence,prescription patterns,and determinants of antipsychotic use in patients with Parkinson's disease

Empirical data regarding the choice of antipsychotics for the management of psychosis in patients with Parkinson's disease are limited. This study aimed to evaluate the incidence and prescribing patterns of antipsychotics and to determine the predictors associated with the prescribing of typical antipsychotics in patients with Parkinson's disease. This was a retrospective cohort study analyzing data from the National Health Insurance Research Database in Taiwan between January 1, 2000, and December 31, 2006, in which patients with Parkinson's disease (ICD‐9‐CM codes 332) initially receiving any antiparkinsonian drug (n = 2095) were followed up to evaluate the subsequent use of antipsychotics. Kaplan–Meier statistics and multiple logistic regression were employed to evaluate the cumulative probability of antipsychotic use and determinants of prescribing of typical antipsychotics, respectively. The cumulative probability of initiation of an antipsychotic within 6 years was found to be 51%, and the proportion of patients who began taking an atypical antipsychotic increased from 11.1% in 2001 to 36.1% in 2005. Physician specialty was found to be the most influential predictor of the prescribing of typical antipsychotics: physicians with an internal medicine specialty were 10.62 times more likely (95% confidence interval, 4.64–24.32) to prescribe typical antipsychotics than were neurologists. The use of antipsychotics in Parkinson's disease is common, and the use of typical antipsychotics dominates antipsychotic treatment. Particular attention needs to be paid to improving practice, including efforts that encourage primary care providers to have the appropriate choice of antipsychotics in patients with Parkinson's disease. © 2011 Movement Disorder Society     

Uncovering novel actors in astrocyte–neuron crosstalk in Parkinson's disease: the Wnt/β‐catenin signaling cascade as the common final pathway for neuroprotection and self‐repair

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neuronal cell bodies in the substantia nigra pars compacta and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are ill‐defined, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD pathophysiology, playing both protective and destructive roles. Here, the contribution of reactive astrocytes and their ability to modulate DAergic neurodegeneration, neuroprotection and neurorepair in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) rodent model of PD will be discussed in the light of novel emerging evidence implicating wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin signaling as a strong candidate in MPTP‐induced nigrostriatal DAergic plasticity. In this work, we highlight an intrinsic Wnt1/frizzled‐1/β‐catenin tone that critically contributes to the survival and protection of adult midbrain DAergic neurons, with potential implications for drug design or drug action in PD. The dynamic interplay between astrocyte‐derived factors and neurogenic signals in MPTP‐induced nigrostriatal DAergic neurotoxicity and repair will be summarized, together with recent findings showing a critical role of glia–neural stem/progenitor cell (NPC) interactions aimed at overcoming neurodegeneration and inducing neurorestoration. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and deciphering the signals facilitating the crosstalk between astrocytes, microglia, DAergic neurons and NPCs may have major implications for the role of stem cell technology in PD, and for identifying potential therapeutic targets to induce endogenous neurorepair.     

Pathogenic role of glial cells in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Alternatively, this glial response can also mediate a variety of deleterious events related to the production of pro-oxidant reactive species, and pro-inflammatory prostaglandin and cytokines. We discuss the potential protective and deleterious effects of glial cells in the SNpc of PD and examine how those factors may contribute to the pathogenesis of this disease.     

Role of the VPS35 D620N mutation in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder involving the loss of dopaminergic neurons in the brain. Following the discovery of the PD-causing D620N mutation in the VPS35 (Vacuolar sorting protein 35) gene, dysfunction in the subcellular retromer complex has been strongly implicated in pathogenesis of PD. Although the function and dysfunction of the retromer has been a focus of study for some time, the role of this complex in the development of PD is not fully understood. Investigating cellular alterations that occur when the retromer is rendered dysfunctional, such as when the D620N disease-causing mutation is introduced into various model systems, shows that endosomal processing defects are major contributors to the disease phenotype. Altered trafficking of retromer cargo molecules, reduced cellular survival and altered processing of alpha-synuclein have all been observed in the presence of the D620N mutation. In addition, interactions between the retromer and the protein products of other familial Parkinsonism-related genes, has made the retromer a prime target of research in PD. This review gives an overview of the changes in retromer function, identified thus far, that may contribute to the neurodegeneration observed in PD.     

Radical formation site of cerebral complex I and Parkinson's disease

Paraquat was reduced to the paraquat radical via complex I in bovine cerebral mitochondria and accelerated lipid peroxidation. Thirty-kilodalton subunit of complex I was considered to be the radical formation site, because of its marked destruction by the paraquat radical. The lipid peroxidation by the paraquat radical was suppressed not only by superoxide dismutase (SOD) but also by mannitol. The destruction of complex I subunits via lipid peroxidation must have been caused by the hydroxyl radical which was formed from the superoxide radical. The same phenomenon was observed by using 1-methylnicotinamide (MNA), which contains the same partial structure as paraquat in itself and is metabolized from nicotinamide in a living body. We observed NADH oxidation by MNA via cerebral complex I (Km = 26.3 mM), and MNA destroyed some complex I subunits, especially 30-kilodalton protein. Paraquat might be useful for studying the pathogenesis of Parkinson's disease (PD) in vitro, and MNA is expected to be one of the causal substances of PD from the viewpoint of the oxidative stress theory. © 1995 Wiley-Liss, Inc.     

Association between Parkinson's disease and the HLA‐DRB1 locus

Two genome‐wide association studies (GWASs) recently highlighted the HLA‐DRA and HLA‐DRB5 genes as associated with Parkinson disease (PD). However, because HLA‐DRA displays a low level of polymorphisms and HLA‐DRB5 is only present in approximately 20% of the population, these findings are difficult to interpret. Our aims were: (1) to replicate and investigate in greater detail the association between PD and the HLA‐DR region; (2) to identify PD‐associated HLA alleles; and (3) to perform a meta‐analysis of our top finding. As part of 2 French population‐based case–control studies of PD including highly ethnically homogeneous participants, we investigated the association between PD and 51 Single‐nucleotide polymorphisms (SNPs) in the HLA‐DR region. HLA‐DRB1 alleles were imputed using the HLA^*IMP software. HLA typing was performed in a subsample of the participants. We performed a meta‐analysis of our top finding based on 4 GWAS data sets. Among 499 cases and 1123 controls, after correction for multiple testing, we found an association with rs660895 (OR/minor allele, 0.70; 95% CI, 0.57–0.87) within the HLA‐DRB1 gene, which encodes the most polymorphic HLA‐DR chain (DRβ). A meta‐analysis (7996 cases, 36455 controls) confirmed this association (OR, 0.86; 95% CI, 0.82–0.91; P < .0001). SNP‐based imputation of HLA alleles showed an inverse association between PD and the HLA‐DRB1^*04 allele. We replicated an association between PD and the HLA‐DR region and provided further insight into the loci and alleles involved. The highly polymorphic HLA‐DRB1 locus contains rs660895, which represents a more legitimate candidate than previous ones. Our finding is in agreement with the hypothesis of an immune component in PD pathophysiology. © 2012 Movement Disorder Society     

Prevalence and clinical profile of restless legs syndrome in Parkinson's disease

Parkinson's disease (PD) and restless legs syndrome (RLS) have a dopaminergic link. More insight in the clinical profile of RLS in patients with PD may benefit our understanding of this link. The aims of this study were to evaluate the frequency and clinical profile of RLS in a large cohort of PD patients. In 269 nondemented Caucasian PD patients, the four diagnostic criteria for RLS were administered by a RLS trained researcher. In patients with definite RLS, the severity of these symptoms was assessed. Furthermore, in all patients, relevant motor and nonmotor symptoms in PD were evaluated. Definite RLS was present in 11% of the patients. RLS patients were more often female (69% vs. 32%, P < 0.001), but no other significant differences existed between PD patients with and without RLS. Within the PD patients with RLS, severity of RLS correlated positively with PD severity, motor fluctuations, depressive symptoms, daytime sleepiness, cognitive problems, autonomic symptoms, and psychotic symptoms. This study in a large PD cohort shows that prevalence of RLS is similar to that in the general population, which might be caused by underestimation of RLS due to dopaminergic treatment. No relations were found between the presence of RLS and PD symptoms, but the severity of RLS was related to the severity of PD‐related, mainly nondopaminergic, symptoms. It is hypothesized that, nondopaminergic systems, such as the noradrenergic system may play a role in the possible link between PD and RLS. © 2010 Movement Disorder Society     

An updated review of Parkinson's disease genetics and clinicopathological correlations

Knowledge regarding the pathophysiological basis of Parkinson's disease (PD) has been greatly expanded over the past two decades, with extraordinary contributions from the field of genetics. However, genetic classifications became complex, difficult to follow, and at times misleading, by placing well‐established monogenic forms of the disease along with others associated with risk loci, often ill characterized. The present paper summarizes the genetic, clinical, and neuropathological findings of the currently described monogenic forms of PD and also approaches the progress made in determining genetic risk factors for PD. Furthermore, the text incorporates the data into a recently proposed classification system that will hopefully bring a “user‐friendly” approach to this issue. This paper also highlights a number of inconsistencies regarding classification of PD as a single, unique clinicopathological entity—in fact, in order to achieve the development of truly innovative therapies, PD should probably be regarded clinically as a “Parkinson's disease cluster”, instead of a single disease. In the future, we hope that an in‐depth and groundbreaking understanding of PD will allow the development of truly disease‐modifying therapies that will target the molecular processes responsible for the cascade of pathological events underlying each form of PD.     

Animal models of Parkinson's disease: Similarities and differences between the disease and models

Parkinson's disease (PD) is a progressive movement disorder characterized by resting tremor, rigidity, akinesia, and postural instability. In addition, PD is characterized by the appearance of Lewy bodies in the remaining neurons. The exact etiology for this disease is still unknown. However, genetic–environmental interaction could contribute to the pathomechanisms of PD. Indeed, seven causative genes responsible for familial PD have been identified. Since discovery of familial PD (FPD), genetic PD models have been developed. Moreover, new PD models using neurotoxins have been reported. In this review, the similarities between human PD and PD models such as genetic mice and Drosophila models are reviewed.     

The role of ATP13A2 in Parkinson's disease: Clinical phenotypes and molecular mechanisms

The importance of ATP13A2 (PARK9) in Parkinson's disease (PD) has emerged with the discovery that mutations in this gene cause Kufor‐Rakeb syndrome, an autosomal recessive, juvenile‐onset form of parkinsonism associated with the additional clinical triad of spasticity, supranuclear gaze palsy, and dementia. Eleven independent kindreds with homozygous or compound heterozygous ATP13A2 mutations have been identified. These reports make it clear that the condition exhibits considerable clinical heterogeneity, with a spectrum of disease even among family members carrying the same mutation. The relevance of the protein in sporadic PD is demonstrated by the presence of single heterozygous ATP13A2 mutations in this group of patients and altered expression of the gene in the substantia nigra from patients with the disease. The involvement of ATP13A2 in Zn²⁺ homeostasis has recently been demonstrated, with the molecular consequences of this disturbance causing lysosomal impairment, α‐synuclein accumulation, and mitochondrial dysfunction. These discoveries provide a new understanding of the role that ATP13A2 plays in the development of PD and identify a therapeutic target that may ameliorate α‐synuclein accumulation and lysosomal and mitochondrial dysfunction in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society