Proteomics in human Parkinson's disease research

During the last decades, considerable advances in the understanding of specific mechanisms underlying neurodegeneration in Parkinson's disease have been achieved, yet neither definite etiology nor unifying sequence of molecular events has been formally established. Current unmet needs in Parkinson's disease research include exploring new hypotheses regarding disease susceptibility, occurrence and progression, identifying reliable diagnostic, prognostic and therapeutic biomarkers, and translating basic research into appropriate disease-modifying strategies. The most popular view proposes that Parkinson's disease results from the complex interplay between genetic and environmental factors and mechanisms believed to be at work include oxidative stress, mitochondrial dysfunction, excitotoxicity, iron deposition and inflammation. More recently, a plethora of data has accumulated pinpointing an abnormal processing of the neuronal protein α-synuclein as a pivotal mechanism leading to aggregation, inclusions formation and degeneration. This protein-oriented scenario logically opens the door to the application of proteomic strategies to this field of research. We here review the current literature on proteomics applied to Parkinson's disease research, with particular emphasis on pathogenesis of sporadic Parkinson's disease in humans. We propose the view that Parkinson's disease may be an acquired or genetically-determined brain proteinopathy involving an abnormal processing of several, rather than individual neuronal proteins, and discuss some pre-analytical and analytical developments in proteomics that may help in verifying this concept.     

Systems-Based Analyses of Brain Regions Functionally Impacted in Parkinson's Disease Reveals Underlying Causal Mechanisms

Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum, and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson''s disease. We undertook functional and causal pathway analysis of gene expression and proteomic alterations in these three regions, and the data revealed pathways that correlated with disease progression. In addition, microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release, and these and other changes were reflected across all brain regions. Importantly, subsets of these changes were replicated in Parkinson''s disease blood; suggesting peripheral tissue may provide important avenues for understanding and measuring disease status and progression. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany functional loss and alpha-synuclein pathology in Parkinson''s disease, and may be instrumental to understand, diagnose and follow Parkinson''s disease progression.     

Neurodegeneration in Parkinson's Disease: Interactions of Oxidative Stress,Tryptophan Catabolites and Depression with Mitochondria and Sirtuins

The biological underpinnings to the etiology and course of neurodegeneration in Parkinson's disease are an area of extensive research that has yet to produce an early biological marker or disease-slowing or preventative treatment. Recent conceptualizations of Parkinson's disease have integrated immuno-inflammation and oxidative and nitrosative stress occurring in depression, somatization and peripheral inflammation into the course of Parkinson's disease. We review the data showing the importance of immuno-inflammatory processes and oxidative and nitrosative stress in such classically conceived ‘comorbidities’, suggesting that lifetime, prodromal and concurrent depression and somatization may be intricately involved in the etiology and course of Parkinson's disease, rather than psychiatric comorbidities. This produces a longer term developmental perspective of Parkinson's disease, which incorporates tryptophan catabolites (TRYCATs), lipid peroxidation, sirtuins, cyclic adenosine monophosphate, aryl hydrocarbon receptor, and circadian genes. This integrates wider bodies of data pertaining to neuronal loss in Parkinson's disease, emphasizing how these interact with susceptibility genes to drive changes in mitochondria, blood–brain barrier permeability and intercellular signalling. We review this data here in the context of neurodegeneration in Parkinson's disease and to the future directions indicated for slowing disease progression.     

感染在神经退行性疾病中的调控机制

神经退行性疾病以突触丢失和神经元死亡为特征,表现为认知功能下降、痴呆和运动功能丧失。流行病学和实验证据提示:慢性细菌、病毒和真菌感染可能是导致神经退行性疾病如阿尔兹海默症(AD)、帕金森病(PD)、肌萎缩性侧索硬化症(ALS)和多发性硬化症(MS)等的危险因素。病原体在中枢神经系统的持续感染可导致一系列细胞生物学功能的异常,如诱导蛋白质的错误折叠和聚集、导致氧化应激损伤、细胞自噬异常以及神经元凋亡和坏死等;感染还会触发炎症介质释放并激活宿主免疫应答;此外,感染还可引起慢性神经炎症并导致能量代谢障碍等。本文就感染在神经退行性疾病中的作用机制及其研究进展作一综述,从而为科研人员开发新的药物和治疗方法提供新思路。     

Increased Ndfip1 in the Substantia Nigra of Parkinsonian Brains Is Associated with Elevated Iron Levels

Iron misregulation is a central component in the neuropathology of Parkinson''s disease. The iron transport protein DMT1 is known to be increased in Parkinson''s brains linking functional transport mechanisms with iron accumulation. The regulation of DMT1 is therefore critical to the management of iron uptake in the disease setting. We previously identified post-translational control of DMT1 levels through a ubiquitin-mediated pathway led by Ndfip1, an adaptor for Nedd4 family of E3 ligases. Here we show that loss of Ndfip1 from mouse dopaminergic neurons resulted in misregulation of DMT1 levels and increased susceptibility to iron induced death. We report that in human Parkinson''s brains increased iron concentrations in the substantia nigra are associated with upregulated levels of Ndfip1 in dopaminergic neurons containing α-synuclein deposits. Additionally, Ndfip1 was also found to be misexpressed in astrocytes, a cell type normally devoid of this protein. We suggest that in Parkinson''s disease, increased iron levels are associated with increased Ndfip1 expression for the regulation of DMT1, including abnormal Ndfip1 activation in non-neuronal cell types such as astrocytes.     

Synaptic proteostasis in Parkinson's disease

There are over 7 million people worldwide suffering from Parkinson's disease, and this number will double in the next decade. Causative mutations and risk variants in >20 genes that predominantly act at synapses have been linked to Parkinson's disease. Synaptic defects precede neuronal death. However, we are only now beginning to understand which molecular mechanisms contribute to this synaptic dysfunction. In this review, we discuss recent data demonstrating that Parkinson proteins act centrally to various protein quality control pathways at the synapse, and we argue that disturbed synaptic proteostasis is an early driver of neurodegeneration in Parkinson's disease.     

A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's brains and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor cells

Background

In Parkinson's disease there is progressive loss of dopamine containing neurons in the substantia nigra pars compacta. The neuronal damage is not limited to the substantia nigra but progresses to other regions of brain, leading to loss of motor control as well as cognitive abnormalities. The purpose of this study was to examine causes of progressive damage in the caudate nucleus, which plays a major role in motor coordination and cognition, in experimental Parkinson's disease.

Results

Using chronic 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine treatment of rhesus monkeys to model Parkinson's disease, we found a upregulation of Cathepsin D, a lysosomal aspartic protease, in the caudate nucleus of treated monkeys. Immunofluorescence analysis of caudate nucleus brain tissue showed that the number of lysosomes increased concurrently with the increase in Cathepsin D in neurons. In vitro overexpression of Cathepsin D in a human neuroblastoma cell line led to a significant increase in the number of the lysosomes. Such expression also resulted in extralysosomal Cathepsin D and was accompanied by significant neuronal death associated with caspase activation. We examined apoptotic markers and found a strong correlation of Cathepsin D overexpression to apoptosis.

Conclusions

Following damage to the substantia nigra resulting in experimental Parkinson's disease, we have identified pathological changes in the caudate nucleus, a likely site of changes leading to the progression of disease. Cathepsin D, implicated in pathogenic mechanisms in other disorders, was increased, and our in vitro studies revealed its overexpression leads to cellular damage and death. This work provides important clues to the progression of Parkinson's, and provides a new target for strategies to ameliorate the progression of this disease.     

Synphilin Isoforms and the Search for a Cellular Model of Lewy Body Formation in Parkinson's Disease

A common finding in many neurodegenerative diseases is the presence of inclusion bodies made of aggregated proteins in neurons of affected brain regions. In Parkinson's disease, the inclusion bodies are referred to as Lewy bodies and their main component is α-synuclein. Although many studies have suggested that inclusion bodies may be cell protective, it is still not clear whether Lewy bodies promote or inhibit dopaminergic cell death in Parkinson's disease. Synphilin-1 interacts with α-synuclein and is present in Lewy bodies. Accumulation of ubiquitylated synphilin-1 leads to massive formation of inclusion bodies, which resemble Lewy bodies by their ability to recruit α-synuclein. We have recently isolated an isoform of synphilin-1, synphilin-1A, that spontaneously aggregates in cells, and is present in detergent-insoluble fractions of brain protein samples from α-synucleinopathy patients. Synphilin-1A displays marked neuronal toxicity and, upon proteasome inhibition, accumulates into ubiquitylated inclusions with concomitant reduction of its intrinsic toxicity. The fact that α-synuclein interacts with synphilin-1A, and is recruited to synphilin-1A inclusion bodies in neurons together with synphilin-1, further indicates that synphilin-1A cell model is relevant for research on Parkinson's disease. Synphilin-1A cell model may help provide important insights regarding the role of inclusion bodies in Parkinson's disease and other neurodegenerative disorders.     

Vocal responses to perturbations in voice auditory feedback in individuals with Parkinson's disease

Background

One of the most common symptoms of speech deficits in individuals with Parkinson''s disease (PD) is significantly reduced vocal loudness and pitch range. The present study investigated whether abnormal vocalizations in individuals with PD are related to sensory processing of voice auditory feedback. Perturbations in loudness or pitch of voice auditory feedback are known to elicit short latency, compensatory responses in voice amplitude or fundamental frequency.

Methodology/Principal Findings

Twelve individuals with Parkinson''s disease and 13 age- and sex- matched healthy control subjects sustained a vowel sound (/α/) and received unexpected, brief (200 ms) perturbations in voice loudness (±3 or 6 dB) or pitch (±100 cents) auditory feedback. Results showed that, while all subjects produced compensatory responses in their voice amplitude or fundamental frequency, individuals with PD exhibited larger response magnitudes than the control subjects. Furthermore, for loudness-shifted feedback, upward stimuli resulted in shorter response latencies than downward stimuli in the control subjects but not in individuals with PD.

Conclusions/Significance

The larger response magnitudes in individuals with PD compared with the control subjects suggest that processing of voice auditory feedback is abnormal in PD. Although the precise mechanisms of the voice feedback processing are unknown, results of this study suggest that abnormal voice control in individuals with PD may be related to dysfunctional mechanisms of error detection or correction in sensory feedback processing.     

Parkinson's disease: convergence on synaptic homeostasis

Parkinson's disease, the second most common neurodegenerative disorder, affects millions of people globally. There is no cure, and its prevalence will double by 2030. In recent years, numerous causative genes and risk factors for Parkinson's disease have been identified and more than half appear to function at the synapse. Subtle synaptic defects are thought to precede blunt neuronal death, but the mechanisms that are dysfunctional at synapses are only now being unraveled. Here, we review recent work and propose a model where different Parkinson proteins interact in a cell compartment‐specific manner at the synapse where these proteins regulate endocytosis and autophagy. While this field is only recently emerging, the work suggests that the loss of synaptic homeostasis may contribute to neurodegeneration and is a key player in Parkinson's disease.     

p13 protects against Parkinson's disease

Mitochondrial dysfunction is thought to contribute to Parkinson's disease progression, and factors that can overcome mitochondrial defects could potentially be used to combat the disease and prevent neuronal death. In this issue, Inoue et al 1 report that reduction of p13, a mitochondrial protein that inhibits complex I assembly, rescues the cellular and behavioral defects of Parkinson's disease models. This work suggests that stabilizing the mitochondrial electron transport chain may be beneficial in the context of Parkinson's disease.     

维生素D及其受体在帕金森病中的作用

帕金森病(Parkinson's disease,PD)是一种常见的中枢神经系统退行性疾病,引起帕金森病的发病机制至今尚未明确。帕金森病患者及老年人普遍存在维生素D缺乏,这可能是帕金森病的重要发病机制之一。由于维生素D具有免疫调节,抗氧化,调节神经营养因子,降低神经毒性的功能,能同时针对几种导致神经退行性病变因素发挥作用,特别是老年人纠正维生素D缺乏可能会阻止神经元的损失和PD相关的认知功能下降。因此补充维生素D可能成为治疗PD的方法。近年来研究发现,维生素D受体基因多态性与帕金森病的发病有相关性。该文就维生素D及其受体在帕金森病中可能发生的保护作用及其机制作一综述。     

The neurotoxicity of iron,copper and manganese in Parkinson's and Wilson's diseases

Impaired cellular homeostasis of metals, particularly of Cu, Fe and Mn may trigger neurodegeneration through various mechanisms, notably induction of oxidative stress, promotion of α-synuclein aggregation and fibril formation, activation of microglial cells leading to inflammation and impaired production of metalloproteins. In this article we review available studies concerning Fe, Cu and Mn in Parkinson's disease and Wilson's disease. In Parkinson's disease local dysregulation of iron metabolism in the substantia nigra (SN) seems to be related to neurodegeneration with an increase in SN iron concentration, accompanied by decreased SN Cu and ceruloplasmin concentrations and increased free Cu concentrations and decreased ferroxidase activity in the cerebrospinal fluid. Available data in Wilson's disease suggest that substantial increases in CNS Cu concentrations persist for a long time during chelating treatment and that local accumulation of Fe in certain brain nuclei may occur during the course of the disease. Consequences for chelating treatment strategies are discussed.     

Multiple Modes of Impulsivity in Parkinson's Disease

Cognitive problems are a major factor determining quality of life of patients with Parkinson''s disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson''s disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson''s disease patients (Hoehn and Yahr stage I–III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson''s disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson''s disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson''s disease will support more evidence-based and effective strategies to treat impulsivity.     

CSF-PR 2.0: An Interactive Literature Guide to Quantitative Cerebrospinal Fluid Mass Spectrometry Data from Neurodegenerative Disorders

The rapidly growing number of biomedical studies supported by mass spectrometry based quantitative proteomics data has made it increasingly difficult to obtain an overview of the current status of the research field. A better way of organizing the biomedical proteomics information from these studies and making it available to the research community is therefore called for. In the presented work, we have investigated scientific publications describing the analysis of the cerebrospinal fluid proteome in relation to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Based on a detailed set of filtering criteria we extracted 85 data sets containing quantitative information for close to 2000 proteins. This information was made available in CSF-PR 2.0 (http://probe.uib.no/csf-pr-2.0), which includes novel approaches for filtering, visualizing and comparing quantitative proteomics information in an interactive and user-friendly environment. CSF-PR 2.0 will be an invaluable resource for anyone interested in quantitative proteomics on cerebrospinal fluid.     

Neurotrophic factor therapy for nervous system degenerative diseases

The ability of neurotrophic factors to regulate developmental neuronal survival and adult nervous system planticity suggests the use of these molecuales to treat neurodegeneration associated with human diseases. Solid rationales exist for the use of NGF and neurotrophin-3 in the treatment of neuropathies of the peripheral sensory system, insulin-like growth factor and ciliary neurotrophic factor in motor neuron atrophy, and NGF in Alzheimer's disease. Growth factors have been identified for neurons affected in Parkinson's disease, Huntington's disease, and acute brain and spinal cord injury. Various strategies are actively pursued to deliver neurotrophic factors to the brain, and develop therapeutically useful molecules that mimic neurotrophic factor actions or stimulate their production or receptor mechanisms. 1994 John Wiley & Sons, Inc.     

Potential Mechanisms for Imperfect Synchronization in Parkinsonian Basal Ganglia

Neural activity in the brain of parkinsonian patients is characterized by the intermittently synchronized oscillatory dynamics. This imperfect synchronization, observed in the beta frequency band, is believed to be related to the hypokinetic motor symptoms of the disorder. Our study explores potential mechanisms behind this intermittent synchrony. We study the response of a bursting pallidal neuron to different patterns of synaptic input from subthalamic nucleus (STN) neuron. We show how external globus pallidus (GPe) neuron is sensitive to the phase of the input from the STN cell and can exhibit intermittent phase-locking with the input in the beta band. The temporal properties of this intermittent phase-locking show similarities to the intermittent synchronization observed in experiments. We also study the synchronization of GPe cells to synaptic input from the STN cell with dependence on the dopamine-modulated parameters. Earlier studies showed how the strengthening of dopamine-modulated coupling may lead to transitions from non-synchronized to partially synchronized dynamics, typical in Parkinson''s disease. However, dopamine also affects the cellular properties of neurons. We show how the changes in firing patterns of STN neuron due to the lack of dopamine may lead to transition from a lower to a higher coherent state, roughly matching the synchrony levels observed in basal ganglia in normal and parkinsonian states. The intermittent nature of the neural beta band synchrony in Parkinson''s disease is achieved in the model due to the interplay of the timing of STN input to pallidum and pallidal neuronal dynamics, resulting in sensitivity of pallidal output to the phase of the arriving STN input. Thus the mechanism considered here (the change in firing pattern of subthalamic neurons through the dopamine-induced change of membrane properties) may be one of the potential mechanisms responsible for the generation of the intermittent synchronization observed in Parkinson''s disease.     

Using induced pluripotent stem cell neuronal models to study neurodegenerative diseases

Current application of human induced pluripotent stem cells (hiPSCs) technology in patient-specific models of neurodegenerative disorders recapitulate some of key phenotypes of diseases, representing disease-specific cellular modeling and providing a unique platform for therapeutics development. We review recent efforts toward advancing hiPSCs-derived neuronal cell types and highlight their potential use for the development of more complex in vitro models of neurodegenerative diseases by focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. We present evidence from previous works on the important phenotypic changes of various neuronal types in these neurological diseases. We also summarize efforts on conducting low- and high-throughput screening experiments with hiPSCs toward developing potential therapeutics for treatment of neurodegenerative diseases. Lastly, we discuss the limitations of hiPSCs culture system in studying neurodegenerative diseases and alternative strategies to overcome these hurdles.     

Parkinson's disease as a result of aging

It is generally considered that Parkinson's disease is induced by specific agents that degenerate a clearly defined population of dopaminergic neurons. Data commented in this review suggest that this assumption is not as clear as is often thought and that aging may be critical for Parkinson's disease. Neurons degenerating in Parkinson's disease also degenerate in normal aging, and the different agents involved in the etiology of this illness are also involved in aging. Senescence is a wider phenomenon affecting cells all over the body, whereas Parkinson's disease seems to be restricted to certain brain centers and cell populations. However, reviewed data suggest that Parkinson's disease may be a local expression of aging on cell populations which, by their characteristics (high number of synaptic terminals and mitochondria, unmyelinated axons, etc.), are highly vulnerable to the agents promoting aging. The development of new knowledge about Parkinson's disease could be accelerated if the research on aging and Parkinson's disease were planned together, and the perspective provided by gerontology gains relevance in this field.