Particularly Parkinson's Disease Research Articles

L-DOPA Promotes Functional Proliferation Through GPR143, Specific L-DOPA Receptor of Astrocytes.

l-3,4-Dihydroxyphenylalanine (levodopa and L-DOPA in this text), alongside dopamine, boasts high biocompatibility, prompting industrial demand for its use as a coating material. Indeed, the effectiveness of L-DOPA is steadily rising as it serves as an oral therapeutic agent for neurodegenerative brain diseases, particularly Parkinson's disease (PD). However, the effects of L-DOPA on the growth and function of astrocytes, the main glial cells, and the most numerous glial cells in the brain, are unknown. Here, we investigated whether L-DOPA is possible as a coating material on cover glass and polystyrene for rat primary astrocytes. The coating state of L-DOPA on the cover glass and polystyrene was characterized by X-ray photoelectron spectroscopy (XPS) and static water contact angle (WCA). Interestingly, L-DOPA coated on the cover glass promoted the proliferation of astrocytes but not neurons. Furthermore, L-DOPA coated on the cover glass, as opposed to polystyrene, facilitated the proliferation of the astrocytes. The astrocytes grown on L-DOPA-coated cover glasses exhibited functional receptor-activated Ca2+ transients through the activation of protease-activated receptor subtype 1 (PAR-1), recognized as an astrocytic functional marker. However, cover glass coated with 0, 500, 1000, 2000, and 4000 μg/mL L-DOPA maintained astrocyte viability, while supplementation with 500 and 1000 μM L-DOPA significantly decreased astrocyte viability. This suggests that treatments with free 500 and 1000 μM L-DOPA significantly reduced the number of astrocytes. Both Pimozide, an inhibitor of G protein-coupled receptor 143 (GPR143), also known as Ocular albinism type 1 (OA1), and CCG2046, an inhibitor of regulator of G protein signaling 4 (RGS4), reduced the viability of astrocytes on cover glass coated with L-DOPA compared to astrocytes on cover glass coated with poly-d-lysine (PDL). This suggests that L-DOPA promotes astrocyte proliferation through activation of the GPR143 signaling pathway. These findings imply that L-DOPA proliferates functional astrocytes through the activation of GPR143. These results are the first report that L-DOPA coating cover glass proliferates rat primary astrocytes with the activation of GPR143. The discovery that levodopa enhances cell adhesion can significantly influence research in multiple ways. It provides insights into cell behavior, disease mechanisms, and potential therapeutic applications in tissue engineering and regenerative medicine. Additionally, it offers opportunities to explore novel approaches for improving cell-based therapies and tissue regeneration. Overall, this finding opens up new avenues for research, with broad implications across various scientific fields.

Amplitude Adaptive Modulation of Neural Oscillations Over Long-Term Dynamic Conditions: A Computational Study.

Closed-loop deep brain stimulation (DBS) shows great potential for precise neuromodulation of various neurological disorders, particularly Parkinson's disease (PD). However, substantial challenges remain in clinical translation due to the complex programming procedure of closed-loop DBS parameters. In this study, we proposed an online optimized amplitude adaptive strategy based on the particle swarm optimization (PSO) and proportional-integral-differential (PID) controller for modulation of the beta oscillation in a PD mean field model over long-term dynamic conditions. The strategy aimed to calculate the stimulation amplitude adapting to the fluctuations caused by circadian rhythm, medication rhythm, and stochasticity in the basal ganglia-thalamus-cortical circuit. The PID gains were optimized online using PSO, based on modulation accuracy, mean stimulation amplitude, and stimulation variation. The results showed that the proposed strategy optimized the stimulation amplitude and achieved beta power modulation under the influence of circadian rhythm, medication rhythm, and stochasticity of beta oscillations. This work offers a novel approach for precise neuromodulation with the potential for clinical translation.

Closed-Loop Deep Brain Stimulation With Reinforcement Learning and Neural Simulation.

Deep Brain Stimulation (DBS) is effective for movement disorders, particularly Parkinson's disease (PD). However, a closed-loop DBS system using reinforcement learning (RL) for automatic parameter tuning, offering enhanced energy efficiency and the effect of thalamus restoration, is yet to be developed for clinical and commercial applications. In this research, we instantiate a basal ganglia-thalamic (BGT) model and design it as an interactive environment suitable for RL models. Four finely tuned RL agents based on different frameworks, namely Soft Actor-Critic (SAC), Twin Delayed Deep Deterministic Policy Gradient (TD3), Proximal Policy Optimization (PPO), and Advantage Actor-Critic (A2C), are established for further comparison. Within the implemented RL architectures, the optimized TD3 demonstrates a significant 67% reduction in average power dissipation when compared to the open-loop system while preserving the normal response of the simulated BGT circuitry. As a result, our method mitigates thalamic error responses under pathological conditions and prevents overstimulation. In summary, this study introduces a novel approach to implementing an adaptive parameter-tuning closed-loop DBS system. Leveraging the advantages of TD3, our proposed approach holds significant promise for advancing the integration of RL applications into DBS systems, ultimately optimizing therapeutic effects in future clinical trials.

Neuronal-type-specific epigenome editing to decrease SNCA expression: Implications for precision medicine in synucleinopathies

Overexpression of SNCA has been implicated in the pathogenesis of synucleinopathies, particularly Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While PD and DLB share some clinical and pathological similarities, each disease presents distinct characteristics, including the primary affected brain region and neuronal type. We aimed to develop neuronal-type-specific SNCA-targeted epigenome therapies for synucleinopathies. The system is based on an all-in-one lentiviral vector comprised of CRISPR-dSaCas9 and guide RNA (gRNA) targeted at SNCA intron 1 fused with a synthetic repressor molecule of Krüppel-associated box (KRAB)/ methyl CpG binding protein 2 (MeCp2) transcription repression domain (TRD). To achieve neuronal-type specificity for dopaminergic and cholinergic neurons, the system was driven by tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) promoters, respectively. Delivering the system into human induced pluripotent stem cell (hiPSC)-derived dopaminergic and cholinergic neurons from a patient with the SNCA triplication resulted in efficient and neuronal-type-specific downregulation of SNCA-mRNA and protein. Furthermore, the reduction in SNCA levels by the gRNA-dSaCas9-repressor system rescued disease-related cellular phenotypes including Ser129-phophorylated α-synuclein, neuronal viability, and mitochondrial dysfunction. We established a novel neuronal-type-specific SNCA-targeted epigenome therapy and provided invitro proof of concept using human-based disease models. Our results support the therapeutic potential of our system for PD and DLB and provide the foundation for further preclinical studies in animal models toward investigational new drug (IND) enablement and clinical trials.

Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson's Disease.

Neuroinflammation plays a crucial role in the progression of neurodegenerative disorders, particularly Parkinson's disease (PD). Glial cell activation and subsequent adaptive immune involvement are neuroinflammatory features in familial and idiopathic PD, resulting in the death of dopaminergic neuron cells. An oxidative stress response, inflammatory mediator production, and immune cell recruitment and activation are all hallmarks of this activation, leading to chronic neuroinflammation and progressive neurodegeneration. Several studies in PD patients' cerebrospinal fluid and peripheral blood revealed alterations in inflammatory markers and immune cell populations that may lead to or exacerbate neuroinflammation and perpetuate the neurodegenerative process. Most of the genes causing PD are also expressed in astrocytes and microglia, converting their neuroprotective role into a pathogenic one and contributing to disease onset and progression. Nuclear receptor-related transcription factor 1 (NURR1) regulates gene expression linked to dopaminergic neuron genesis and functional maintenance. In addition to playing a key role in developing and maintaining neurotransmitter phenotypes in dopaminergic neurons, NURR1 agonists have been shown to reverse behavioral and histological abnormalities in animal PD models. NURR1 protects dopaminergic neurons from inflammation-induced degeneration, specifically attenuating neuronal death by suppressing the expression of inflammatory genes in microglia and astrocytes. This narrative review highlights the inflammatory changes in PD and the advances in NURR1-regulated neuroinflammation associated with PD. Further, we present new evidence that targeting this inflammation with a variety of potential NURR1 target therapy medications can effectively slow the progression of chronic neuroinflammation-induced PD.

Electrophysiological biomarkers for deep brain stimulation outcomes in movement disorders: state of the art and future challenges

Several neurological diseases are accompanied by rhythmic oscillatory dysfunctions in various frequency ranges and disturbed cross-frequency relationships on regional, interregional, and whole brain levels. Knowledge of these disease-specific oscillopathies is important mainly in the context of deep brain stimulation (DBS) therapy. Electrophysiological biomarkers have been used as input signals for adaptive DBS (aDBS) as well as preoperative outcome predictors. As movement disorders, particularly Parkinson's disease (PD), are among the most frequent DBS indications, the current research of DBS is the most advanced in the movement disorders field. We reviewed the literature published mainly between 2010 and 2020 to identify the most important findings concerning the current evolution of electrophysiological biomarkers in DBS and to address future challenges for prospective research.

Update on the association between alpha‐synuclein and tau with mitochondrial dysfunction: Implications for Parkinson's disease

The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing.

Parkinson's and Alzheimer's diseases: Focus on mild cognitive impairment

The mild cognitive impairment (MCI) concept was developed to identify the earliest stages of cognitive impairment. MCI and, more specifically, amnestic MCI were initially proposed as transitional states that ultimately progress to full blown Alzheimer's disease (AD). However, MCI subjects do not uniformly progress to dementia (either AD or another) and may revert back to normal cognitive state. The MCI as concept has been borrowed from AD to other neurodegenerative diseases, particularly Parkinson's disease (PD). However the operational definition of MCI may not adequately convey the intended concept. Additional modifications to the concept and its operationalization are needed in order to better identify patients with incipient cognitive impairment and to guide clinical and research practices.Patients with PD have a very high likelihood of developing dementia, insidiously over many years. Cognitive impairment may start even before other symptoms.No constellation of cognitive symptoms in an otherwise healthy individual will herald development of AD or indeed will progress to dementia, including PD-dementia, in high likelihood.At present, identification of subtle cognitive dysfunction even in a person with diagnosed PD does not benefit the patient and should be avoided, except for research purposes.

Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model.

Increasing evidence involves sustained pro-inflammatory microglia activation in the pathogenesis of different neurodegenerative diseases, particularly Parkinson's disease (PD). We recently uncovered a completely novel and unexpected role for caspase-8 and its downstream substrates caspase-3/7 in the control of microglia activation and associated neurotoxicity to dopaminergic cells. To demonstrate the genetic evidence, mice bearing a floxed allele ofCASP8 were crossed onto a transgenic line expressing Cre under the control of Lysozyme 2 gene. Analysis of caspase-8 gene deletion in brain microglia demonstrated a high efficiency in activated but not in resident microglia. Mice were challenged with lipopolysaccharide, a potent inducer of microglia activation, or with MPTP, which promotes specific dopaminergic cell damage and consequent reactive microgliosis. In neither of these models, CASP8 deletion appeared to affect the overall number of microglia expressing the pan specific microglia marker, Iba1. In contrast, CD16/CD32 expression, a microglial pro-inflammatory marker, was found to be negatively affected upon CASP8 deletion. Expression of additional proinflammatory markers were also found to be reduced in response to lipopolysaccharide. Of importance, reduced pro-inflammatory microglia activation was accompanied by a significant protection of the nigro-striatal dopaminergic system in the MPTP mouse model of PD.

Analyzing alternative splicing data of splice junction arrays from Parkinson patients' leukocytes before and after deep brain stimulation as compared with control donors.

Few studies so far examined alternative splicing alterations in blood cells of neurodegenerative disease patients, particularly Parkinson's disease (PD). Prototype junction microarrays interrogate known human genome junctions and enable characterization of alternative splicing events; however, the analysis is not straightforward and different methods can be used to estimate junction-specific alternative splicing events (some of which can also be applied for analyzing RNA sequencing junction-level data). In this study, we characterized alternative splicing changes in blood leukocyte samples from Parkinson's patients prior to, and following deep brain stimulation (DBS) treatment; both on stimulation and following 1 h off electrical stimulation. Here, we describe in detail analysis approaches for junction microarrays and provide suggestions for further analyses to delineate transcript level effects of the observed alterations as well as detection of microRNA binding sites and protein domains in the alternatively spliced target regions spanning across both untranslated and the coding regions of the targets. The raw expression data files are publically available in the Gene Expression Omnibus (GEO) database (accession number: GSE37591) and in Synapse, and can be re-analyzed. The results may be useful for designing of future experiments and cross correlations with other datasets from PD or patients having other neurodegenerative diseases.

Olfactory system

The olfactory system has several unique features in terms of mechanisms of sensory transduction, relay, and central processing of information and provides a typical example of functional plasticity.1–5 Olfactory deficits are frequently found in neurodegenerative disorders, particularly Parkinson disease (PD) and Alzheimer disease (AD). The neuropathologic substrate of olfactory dysfunction in neurodegenerative disorders is incompletely elucidated and likely reflects degenerative changes at multiple levels of the olfactory system, including the olfactory epithelium, olfactory bulb, primary olfactory cortices, and their secondary targets.6,7 These issues have been extensively reviewed1–7 and only some salient points are emphasized here. ### Olfactory receptor cells and sensory transduction. The olfactory sensory neurons form clusters interposed among patches of respiratory neuroepithelium.1 These neurons are bipolar cells with a dendritic end containing 3–50 cilia that project into the overlying mucus; their unmyelinated axons form bundles that project through the cribriform plate and synapse in the olfactory bulb.1,2 Odorants bind to guanine nucleotide binding (G) protein–coupled receptors located in the cilia of the olfactory receptor neuron. There are about 400 types of receptors expressed in human olfactory neurons and an individual olfactory sensory neuron typically responds to more than one odorant type.1,5 The first step in olfactory signal transduction is the activation of the Gαolf, which stimulates adenylyl cyclase 3 and production of cyclic adenosyl monophosphate (figure). This triggers opening of a cyclic nucleotide–gated channel allowing calcium (Ca2+) influx and depolarization; subsequent opening of Ca2+ activated chloride (Cl−) channels elicits Cl− efflux that amplifies the depolarization of the sensory neuron.1 The olfactory receptor neurons have several unique features: they can regenerate; serve both as odorant-selective receptor cells and first-order neurons; and are directly exposed to the external environment, thus providing a primary route for invasion into the brain by viruses or toxins.5 …

Integrating multiple aspects of mitochondrial dynamics in neurons: Age-related differences and dynamic changes in a chronic rotenone model

Changes in dynamic properties of mitochondria are increasingly implicated in neurodegenerative diseases, particularly Parkinson's disease (PD). Static changes in mitochondrial morphology, often under acutely toxic conditions, are commonly utilized as indicators of changes in mitochondrial fission and fusion. However, in neurons, mitochondrial fission and fusion occur in a dynamic system of axonal/dendritic transport, biogenesis and degradation, and thus, likely interact and change over time. We sought to explore this using a chronic neuronal model (nonlethal low-concentration rotenone over several weeks), examining distal neurites, which may give insight into the earliest changes occurring in PD. Using this model, in live primary neurons, we directly quantified mitochondrial fission, fusion, and transport over time and integrated multiple aspects of mitochondrial dynamics, including morphology and growth/mitophagy. We found that rates of mitochondrial fission and fusion change as neurons age. In addition, we found that chronic rotenone exposure initially increased the ratio of fusion to fission, but later, this was reversed. Surprisingly, despite changes in rates of fission and fusion, mitochondrial morphology was minimally affected, demonstrating that morphology can be an inaccurate indicator of fission/fusion changes. In addition, we found evidence of subcellular compartmentalization of compensatory changes, as mitochondrial density increased in distal neurites first, which may be important in PD, where pathology may begin distally. We propose that rotenone-induced early changes such as in mitochondrial fusion are compensatory, accompanied later by detrimental fission. As evidence, in a dopaminergic neuronal model, in which chronic rotenone caused loss of neurites before cell death (like PD pathology), inhibiting fission protected against the neurite loss. This suggests that aberrant mitochondrial dynamics may contribute to the earliest neuropathologic mechanisms in PD. These data also emphasize that mitochondrial fission and fusion do not occur in isolation, and highlight the importance of analysis and integration of multiple mitochondrial dynamic functions in neurons.

Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder

<b>Objective:</b> Idiopathic REM sleep behavior disorder (RBD) is a potential preclinical marker for the development of neurodegenerative diseases, particularly Parkinson disease (PD) and Lewy body dementia. However, the long-term risk of developing neurodegeneration in patients with idiopathic RBD has not been established. Obtaining an accurate picture of this risk is essential for counseling patients and for development of potential neuroprotective therapies. <b>Methods:</b> We conducted a follow-up study of all patients seen at the sleep disorders laboratory at the Hôpital du Sacré Coeur with a diagnosis of idiopathic RBD. Diagnoses of parkinsonism and dementia were defined according to standard criteria. Survival curves were constructed to estimate the 5-, 10-, and 12-year risk of developing neurodegenerative disease. <b>Results:</b> Of 113 patients, 93 (82%) met inclusion criteria. The mean age of participants was 65.4 years and 75 patients (80.4%) were men. Over the follow-up period, 26/93 patients developed a neurodegenerative disorder. A total of 14 patients developed PD, 7 developed Lewy body dementia, 4 developed dementia that met clinical criteria for AD, and 1 developed multiple system atrophy. The estimated 5-year risk of neurodegenerative disease was 17.7%, the 10-year risk was 40.6%, and the 12-year risk was 52.4%. <b>Conclusions:</b> Although we have found a slightly lower risk than other reports, the risk of developing neurodegenerative disease in idiopathic REM sleep behavior disorder is substantial, with the majority of patients developing Parkinson disease and Lewy body dementia.

Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder

Idiopathic REM sleep behavior disorder (RBD) is a potential preclinical marker for the development of neurodegenerative diseases, particularly Parkinson disease (PD) and Lewy body dementia. However, the long-term risk of developing neurodegeneration in patients with idiopathic RBD has not been established. Obtaining an accurate picture of this risk is essential for counseling patients and for development of potential neuroprotective therapies. We conducted a follow-up study of all patients seen at the sleep disorders laboratory at the Hôpital du Sacré Coeur with a diagnosis of idiopathic RBD. Diagnoses of parkinsonism and dementia were defined according to standard criteria. Survival curves were constructed to estimate the 5-, 10-, and 12-year risk of developing neurodegenerative disease. Of 113 patients, 93 (82%) met inclusion criteria. The mean age of participants was 65.4 years and 75 patients (80.4%) were men. Over the follow-up period, 26/93 patients developed a neurodegenerative disorder. A total of 14 patients developed PD, 7 developed Lewy body dementia, 4 developed dementia that met clinical criteria for AD, and 1 developed multiple system atrophy. The estimated 5-year risk of neurodegenerative disease was 17.7%, the 10-year risk was 40.6%, and the 12-year risk was 52.4%. Although we have found a slightly lower risk than other reports, the risk of developing neurodegenerative disease in idiopathic REM sleep behavior disorder is substantial, with the majority of patients developing Parkinson disease and Lewy body dementia.

Dopaminergic regeneration by neurturin-overexpressing c17.2 neural stem cells in a rat model of Parkinson's disease

BackgroundGenetically engineered neural stem cell (NSC) lines are promising vectors for the treatment of neurodegenerative diseases, particularly Parkinson's disease (PD). Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family, has been demonstrated to act specifically on mesencephalic dopaminergic neurons, suggesting its therapeutic potential for PD. In our previous work, we demonstrated that NTN-overexpressing c17.2 NSCs exerted dopaminergic neuroprotection in a rat model of PD. In this study, we transplanted NTN-c17.2 into the striatum of the 6-hydroxydopamine (6-OHDA) PD model to further determine the regenerative effect of NTN-c17.2 on the rat models of PD.ResultsAfter intrastriatal grafting, NTN-c17.2 cells differentiated and gradually downregulated nestin expression, while the grafts stably overexpressed NTN. Further, an observation of rotational behavior and the contents of neurotransmitters tested by high-performance liquid chromatography showed that the regenerative effect of the NTN-c17.2 group was significantly better than that of the Mock-c17.2 group, and the regenerative effect of the Mock-c17.2 group was better than that of the PBS group. Further research through reverse-transcriptase polymerase chain reaction assays and in vivo histology revealed that the regenerative effect of Mock-c17.2 and NTN-c17.2 cell grafts may be attributed to the ability of NSCs to produce neurotrophic factors and differentiate into tyrosine hydroxylase-positive cells.ConclusionThe transplantation of NTN-c17.2 can exert neuroregenerative effects in the rat model of PD, and the delivery of NTN by NSCs may constitute a very useful strategy in the treatment of PD.

Homocysteine and Parkinson's disease: A dangerous liaison?

Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) – which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine – are associated with a wide range of clinical manifestations, mostly affecting the central nervous system ( e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.

Neuroimaging and Therapeutics in Movement Disorders

In this review, we discuss the role of neuroimaging in assessing treatment options for movement disorders, particularly Parkinson's disease (PD). Imaging methods to assess dopaminergic function have recently been applied in trials of potential neuroprotective agents. Other imaging methods using regional metabolism and/or cerebral perfusion have been recently introduced to quantify the modulation of network activity as an objective marker of the treatment response. Both imaging strategies have provided novel insights into the mechanisms underlying a variety of pharmacological and stereotaxic surgical treatment strategies for PD and other movement disorders.