Parkinson's Disease Progression Research Articles

Exploratory Analysis of the Association Between Plasma Ceramide Alterations and Cognitive Dysfunction in Parkinson's Disease.

Prior research has underscored the importance of sphingolipid metabolism in Parkinson's disease (PD) pathogenesis. Our objective was to explore the associations between plasma ceramide levels and PD patients with cognitive dysfunction (PD-CD). We enrolled two study populations from Eastern China and the Parkinson's Progression Markers Initiative (PPMI), comprising 290 (100 HCs, 160 PDs, and 30 MSAs) and 429 (125 HCs and 304 PDs) participants, respectively. The plasma levels of ceramides (Cer 16:0, Cer 18:0, Cer 24:0, and Cer 24:1) were tested via HPLC-MS/MS analysis. Compared with those in the HC group, the plasma levels of Cer 18:0, Cer 24:1, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were higher in both the PD and MSA groups. Significant differences in the plasma levels of Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were observed among the PD-NC (PD with normal cognition), PD-MCI (PD with mild cognitive impairment), and PDD (PD dementia) groups, with the PDD group exhibiting the highest levels. PD patients with higher baseline levels of plasma ceramides (specifically, Cer 18:0, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0) demonstrated accelerated cognitive decline compared with individuals who had lower baseline plasma ceramide levels during the 5-year follow-up period. A biomarker panel including Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 could effectively differentiate PD-CD from PD-NC with notable diagnostic accuracy. Our results indicate that plasma ceramide levels could potentially be used as diagnostic biomarkers for PD-CD.

Deep convolutional neural network-based identification and biological evaluation of MAO-B inhibitors

Parkinson's disease (PD) is one of the most prominent motor disorder of adult-onset dementia connected to memory and other cognitive abilities. Individuals with this vicious neurodegenerative condition tend to have an elevated expression of Monoamine Oxidase-B (MAO-B) that catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. This oxidative stress damages mitochondrial DNA and contributes to the progression of PD. To address this, we have developed a deep learning (DL)-based virtual screening protocol for the identification of promising MAO-B inhibitors using Convolutional neural network (ConvNet) based image classification technique by dealing with two unique kinds of image datasets associated with MACCS fingerprints. Following model building and prediction on the Maybridge library, our approach shortlisted the top 11 compounds at the end of molecular docking protocol. Further, the biological validation of the hits identified 4 compounds as promising MAO-B inhibitors. Among these, the compound RF02426 was found to have >50 % inhibition at 10 μM. Additionally, the study also underscored the utility of scaffold analysis as an effective way for evaluating the significance of structurally diverse compounds in data-driven investigations. We believe that our models are able to pick up diverse chemotype and this can be a starting scaffold for further structural optimization with medicinal chemistry efforts in order to improve their inhibition efficacy and be established as novel MAO-B inhibitors in the furture.

Neuroprotective effects of punicalagin and/or micronized zeolite clinoptilolite on manganese-induced Parkinson's disease in a rat model: Involvement of multiple pathways.

Manganism, a central nervous system dysfunction correlated with neurological deficits such as Parkinsonism, is caused by the substantial collection of manganese chloride (MnCl2) in the brain. To explore the neuroprotective effects of natural compounds, namely, micronized zeolite clinoptilolite (ZC) and punicalagin (PUN), either individually or in combination, against MnCl2-induced Parkinson's disease (PD). Fifty male albino rats were divided into 5 groups (Gps). Gp I was used as the control group, and the remaining animals received MnCl2 (Gp II-Gp V). Rats in Gps III and IV were treated with ZC and PUN, respectively. Gp V received both ZC and PUN as previously reported for the solo-treated plants. ZC and/or PUN reversed the depletion of monoamines in the brain and decreased acetyl choline esterase activity, which primarily adjusted the animals' behavior and motor coordination. ZC and PUN restored the balance between glutamate/γ-amino butyric acid content and markedly improved the brain levels of brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and decreased glycogen synthase kinase-3 beta activity. ZC and PUN also inhibited inflammatory and oxidative markers, including nuclear factor kappa-light-chain-enhancer of activated B cells, Toll-like receptor 4, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 and caspase-1. Bcl-2-associated X-protein and B-cell leukemia/lymphoma 2 protein (Bcl-2) can significantly modify caspase-3 expression. ZC and/or PUN ameliorated PD in rats by decreasing the levels of endoplasmic reticulum (ER) stress markers (p-protein kinase-like ER kinase (PERK), glucose-regulated protein 78, and C/EBP homologous protein (CHOP)) and enhancing the levels of an autophagy marker (Beclin-1). ZC and/or PUN mitigated the progression of PD through their potential neurotrophic, neurogenic, anti-inflammatory, antioxidant, and anti-apoptotic activities and by controlling ER stress through modulation of the PERK/CHOP/Bcl-2 pathway.

Targeting the Labile Iron Pool with Engineered DFO Nanosheets to Inhibit Ferroptosis for Parkinson's Disease Therapy.

Ferroptosis in neurons is considered one of the key factors that induces Parkinson's disease (PD), which is caused by excessive iron accumulation in the intracellular labile iron pool (LIP). The iron ions released from the LIP lead to the aberrant generation of reactive oxygen species (ROS) to trigger ferroptosis and exacerbate PD progression. Herein, a pioneering design of multifunctional nanoregulator deferoxamine (DFO)-integrated nanosheets (BDPR NSs) is presented that target the LIP to restrict ferroptosis and protect against PD. The BDPR NSs are constructed by incorporating a brain-targeting peptide and DFO into polydopamine-modified black phosphorus nanosheets. These BDPR NSs can sequester free iron ions, thereby ameliorating LIP overload and regulating iron metabolism. Furthermore, the BDPR NSs can decrease lipid peroxidation generation by mitigating ROS accumulation. More importantly, BDPR NSs can specifically accumulate in the mitochondria to suppress ROS generation and decrease mitochondrial iron accumulation. In vivo experiments demonstrated that the BDPR NSs highly efficiently mitigated dopaminergic neuronloss and its associated behavioral disorders by modulating the LIP and inhibiting ferroptosis. Thus, the BDPR-based nanovectors holds promise as a potential avenue for advancing PD therapy.

Bidirectional interaction between IL and 17A/IL-17RA pathway dysregulation and α-synuclein in the pathogenesis of Parkinson’s disease

Parkinson’s disease (PD) pathogenesis is characterized by α-synuclein (α-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL-17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased α-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in α-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological α-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological α-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and α-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.

Exercise, Neuroprotective Exerkines, and Parkinson's Disease: A Narrative Review.

Parkinson's disease (PD) is a prevalent neurodegenerative disease in which treatment often includes an exercise regimen. Exercise is neuroprotective in animal models of PD, and, more recently, human clinical studies have verified exercise's disease-modifying effect. Aerobic exercise and resistance training improve many of PD's motor and non-motor symptoms, while neuromotor therapy and stretching/flexibility exercises positively contribute to the quality of life in people with PD. Therefore, understanding the role of exercise in managing this complex disorder is crucial. Exerkines are bioactive substances that are synthesized and released during exercise and have been implicated in several positive health outcomes, including neuroprotection. Exerkines protect neuronal cells in vitro and rodent PD models in vivo. Aerobic exercise and resistance training both increase exerkine levels in the blood, suggesting a role for exerkines in the neuroprotective theory. Many exerkines demonstrate the potential for protecting the brain against pathological missteps caused by PD. Every person (people) with Parkinson's (PwP) needs a comprehensive exercise plan tailored to their unique needs and abilities. Here, we provide an exercise template to help PwP understand the importance of exercise for treating PD, describe barriers confronting many PwP in their attempt to exercise, provide suggestions for overcoming these barriers, and explore the role of exerkines in managing PD. In conclusion, exercise and exerkines together create a powerful neuroprotective system that should contribute to slowing the chronic progression of PD.

Mass Spectrometry Analysis of Neurotransmitter Shifting during Neurogenesis and Neurodegeneration of PC12 Cells.

Parkinson's disease (PD) affects movement; however, most patients with PD also develop nonmotor symptoms, such as hyposmia, sleep disorder, and depression. Dopamine levels in the brain have a critical influence on movement control, but other neurotransmitters are also involved in the progression of PD. This study analyzed the fluctuation of neurotransmitters in PC12 cells during neurogenesis and neurodegeneration by performing mass spectrometry. We found that the dopaminergic metabolism pathway of PC12 cells developed vigorously during the neuron differentiation process and that the neurotransmitters were metabolized into 3-methoxytyramine, which was released from the cells. The regulation of the intracellular and extracellular concentrations of adenosine indicated that adenine nucleotides were actively utilized in neural differentiation. Moreover, we exposed the differentiated PC12 cells to rotenone, which is a suitable material for modeling PD. The cells exposed to rotenone in the early stage of differentiation exhibited stimulated serotoninergic metabolism, and the contents of the serotoninergic neurotransmitters returned to their normal levels in the late stage of differentiation. Interestingly, the nondifferentiated cells can resist the toxicant rotenone and produce normal dopaminergic metabolites. However, when differentiated neuron cells were exposed to rotenone, they were seriously damaged, leading to a failure to produce dopaminergic neurotransmitters. In the low-dosage damage process, the amino acids that functioned as dopaminergic pathway precursors could not be absorbed by the cells, and dopamine and L-dopa were secreted and unable to be reuptaken to trigger the cell damage.

Cortical microstructural alterations in different stages of Parkinson's disease.

To explore the cortical microstructural alterations in Parkinson's disease (PD) at different stages.149 PD patients and 76 healthy controls were included. PD patients were divided into early stage PD (EPD) (Hoehn-Yahr stage ≤ 2) and moderate-to-late stage PD (MLPD) (Hoehn-Yahr stage ≥ 2.5) according to their Hoehn-Yahr stages. All participants underwent two-shell diffusion MRI and the images were fitted to Neurite Orientation Dispersion and Density Imaging (NODDI) model to obtain the neurite density index (NDI) and orientation dispersion index (ODI) to reflect the cortical microstructure. We used gray matter-based spatial statistics method to compare the voxel-wise cortical NODDI metrics between groups. Partial correlation was used to correlate the NODDI metrics and global composite outcome in PD patients.Compared with healthy controls, EPD patients showed lower ODI in widespread regions, covering bilateral frontal, temporal, parietal and occipital cortices, as well as regional lower NDI in bilateral cingulate and frontal lobes. Compared with healthy controls, MLPD patients showed lower ODI and NDI in more widespread regions. Compared with EPD patients, MLPD patients showed lower ODI in bilateral temporal, parietal and occipital cortices, where the ODI values were negatively correlated with global composite outcome in PD patients.PD patients showed widespread cortical microstructural degeneration, characterized by reduced neurite density and orientation dispersion, and the cortical neuritic microstructure exhibit progressive degeneration during the progression of PD.

Decoding the Role of Nuclear Sirtuins in Parkinson's Pathogenesis.

Parkinson's disease (PD) is the second most prevailing degenerative disease that deals with dopaminergic neuronal loss and deficiency of dopamine in SNpc and striatum. Manifestations primarily include motor symptoms like tremor, rigidity, and akinesia/dyskinesia along with some nonmotor symptoms like GI and olfactory dysfunction. α-Synuclein pathogenesis is the major cause behind progression of PD; however there are many underlying molecular mechanisms behind the pathophysiology of PD. Sirtuins are small molecular deacetylases that have an imperative role in pathology of such neurodegenerative disorders like PD. Sirtuins are majorly classified according to their location; nuclear (SIRT1,7,6), mitochondrial sirtuins (SIRT3-5), and cytosolic (SIRT2). These actively take part in pathological development and possess independent actions. In this review, the role of nuclear sirtuins is individualistically explored for better understanding of PD pathology and development of advanced therapeutics targeting sirtuins.

Circadian disruption promotes the neurotoxicity of oligomeric alpha-synuclein in mice

Circadian disruption often arises prior to the onset of typical motor deficits in patients with Parkinson’s disease (PD). It remains unclear whether such a prevalent non-motor manifestation would contribute to the progression of PD. Diffusible oligomeric alpha-synuclein (O-αSyn) is perceived as the most toxic and rapid-transmitted species in the early stages of PD. Exploring the factors that influence the spread and toxicity of O-αSyn should be helpful for developing effective interventions for the disease. The aim of this study was to explore the effects of circadian disruption on PD pathology and parkinsonism-like behaviors in a novel mouse model induced by O-αSyn. We discovered that O-αSyn could enter the brain rapidly following intranasal administration, resulting in the formation of nitrated-αSyn pathology and non-motor symptoms of the mice. Meanwhile, circadian disruption exacerbated the burden of nitrated-αSyn pathology and accelerated the loss of dopaminergic neurons in O-αSyn-treated mice. Subsequent experiments demonstrated that circadian disruption might act via promoting nitrative stress and neuroinflammation. These findings could highlight the circadian rhythms as a potential diagnostic and therapeutic target in early-stage PD.

Impact of excessive daytime sleepiness on the progression of freezing of gait in de novo Parkinson's disease: a cohort study.

Excessive daytime sleepiness (EDS) and freezing of gait (FOG) are prevalent non-motor and motor symptoms in patients with Parkinson's disease (PD), significantly impacting their quality of life. However, the correlation between EDS and FOG progression inde novoPD patients remains controversial. A total of 328 participants from the Parkinson's Progression Markers Initiative (PPMI) were divided into two groups: 43 with EDS (EDS group) and 285 without EDS (nEDS group). The cumulative incidence of FOG was assessed at the 5-year follow-up using Kaplan-Meier and log-rank tests. Multivariate Cox proportional hazards models were used to assess the impact of EDS on FOG progression in PD patients, with validation for robustness through sensitivity and subgroup analyses. The EDS group experienced a higher incidence of FOG throughout the 5-year follow-up than did the nEDS group. Multivariate Cox proportional hazards models showed significantly association between EDS severity and enhanced risk of developing FOG (HR = 1.076, 95% CI:1.007 ~ 1.149, P = 0.031). For sensitivity analysis, parallel analyseswere performedby substituting the independent variable with categorical variables, which yielded analogous outcomes (HR = 1.837, 95% CI:1.063 ~ 3.174,P = 0.029). Furthermore, subgroup analyses based on sex, age, TD/PIGD classification, depressive symptoms, cognitive impairment, mean caudate nucleus uptake level, mean putamen nucleus uptake level and CSF Aβ-42 level revealed no significant interactions between subgroups (allPvalues for interaction were > 0.05). EDS is a potential prognosis factor for the progression of FOG in patients with PD.

Functional activity, functional connectivity and complex network biomarkers of progressive hyposmia Parkinson's disease with no cognitive impairment: evidences from resting-state fMRI study.

Olfactory dysfunction stands as one of the most prevalent non-motor symptoms in the initial stage of Parkinson's disease (PD). Nevertheless, the intricate mechanisms underlying olfactory deficits in Parkinson's disease still remain elusive. This study collected rs-fMRI data from 30 PD patients [15 with severe hyposmia (PD-SH) and 15 with no/mild hyposmia (PD-N/MH)] and 15 healthy controls (HC). To investigate functional segregation, the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were utilized. Functional connectivity (FC) analysis was performed to explore the functional integration across diverse brain regions. Additionally, the graph theory-based network analysis was employed to assess functional networks in PD patients. Furthermore, Pearson correlation analysis was conducted to delve deeper into the relationship between the severity of olfactory dysfunction and various functional metrics. We discovered pronounced variations in ALFF, ReHo, FC, and topological brain network attributes across the three groups, with several of these disparities exhibiting a correlation with olfactory scores. Using fMRI, our study analyzed brain function in PD-SH, PD-N/MH, and HC groups, revealing impaired segregation and integration in PD-SH and PD-N/MH. We hypothesize that changes in temporal, frontal, occipital, and cerebellar activities, along with aberrant cerebellum-insula connectivity and node degree and betweenness disparities, may be linked to olfactory dysfunction in PD patients.

Vanillin Mitigates the MPTP-Induced α-Synucleinopathy in a Mouse Model of Parkinson's Disease: Insights into the Involvement of Wnt/β-Catenin Signaling.

The abnormal aggregation of α-synuclein (α-syn) in the substantia nigra pars compacta (SNpc) region of the brain is characteristic of Parkinson's disease (PD), leading to the selective demise of neurons. Modifications in the post-translational processing of α-syn, phosphorylation at Ser129 in particular, are implicated in α-syn aggregation and are considered key hallmarks of PD. Furthermore, dysregulated Wnt/β-catenin signaling, influenced by glycogen synthase kinase-3 beta (GSK-3β), is implicated in PD pathogenesis. Inhibition of GSK-3β holds promise in promoting neuroprotection by enhancing the Wnt/β-catenin pathway. In our previous study utilizing 1-methyl-4-phenylpyridinium (MPP+)-administered differentiated SH-SY5Y cells and a PD mouse model, we explored Vanillin's neuroprotective properties and related mechanisms against neuronal loss induced by MPP+/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. In the current study, we elucidated the mitigating effects of Vanillin on motor impairments, P-Ser129-α-syn expression, Wnt/β-catenin signaling, and autophagic neuron death induced by MPTP in a mouse model of PD by performing motor function tests, western blot analysis and immunostaining. Our results show that Vanillin effectively modulated the motor dysfunctions, GSK-3β expression, and activity, activated the Wnt/β-catenin signaling, and reduced autophagic neuronal demise in the MPTP-lesioned mice, highlighting its neuroprotective effects. These findings underscore the complex interplay between α-syn pathology, GSK-3β, Wnt/β-catenin signaling, and autophagic-cell death in PD pathogenesis. Targeting these pathways, particularly with Vanillin, can be a promising therapeutic strategy for restoring dopaminergic (DA-ergic) neuronal homeostasis and slowing the progression of PD. Further research is crucial to resolving existing disputes and translating these discoveries into effective therapeutic interventions for PD patients.

Liver X receptor α contribution to neuroinflammation and glial cells activation induced by MPTP: Implications for Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder whose etiology remains unknown. The immune system has been implicated in hallmarks of PD including aggregation of α-synuclein and death of dopaminergic neurons in the substantia nigra. As a core regulator of immune response and inflammation, liver X receptors (LXRs) have been shown to have protective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. With two isoforms of LXRs (LXRα and LXRβ) expressed in the brain, their roles and distributions in this tissue remain largely unexplored. Here, we used MPTP to mimic symptoms and biomedical changes seen in PD in LXRα-/- and wild-type mice to investigate the role of LXRα in the etiology and progression of PD. We found that MPTP is unable to induce motor deficits, anxiety-like behavior in LXRα-/- mice, which has been seen in WT mice. Gene ontology analysis of RNA sequencing revealed that knockout of LXRα led to enrichment of the process, including immune response and inflammation in the midbrain. In addition, MPTP did not lead to dopaminergic neuron death in the striatum and substantia nigra in LXRα-/- mice, the basal GFAP protein level, and pro-inflammatory cytokines were elevated in LXRα-/- mice. Lastly, the microglia activation and astrogliosis caused by MPTP intoxication we found in WT mice were abolished in LXRα-/- mice. To sum up, we conclude that LXRα is a critical regulator in MPTP intoxication and may play a unique role in astrogliosis seen in the neuroinflammation of PD.

Cardiovascular dysautonomia and cognitive impairment in Parkinson's disease (Review).

Cognitive impairment is a prevalent non-motor symptom of Parkinson's disease (PD), which can result in significant disability and distress for patients and caregivers. There is a marked variation in the timing, characteristics and rate at which cognitive decline occurs in patients with PD. This decline can vary from normal cognition to mild cognitive impairment and dementia. Cognitive impairment is associated with several pathophysiological mechanisms, including the accumulation of β-amyloid and tau in the brain, oxidative stress and neuroinflammation. Cardiovascular autonomic dysfunctions are commonly observed in patients with PD. These dysfunctions play a role in the progression of cognitive impairment, the incidents of falls and even in mortality. The majority of symptoms of dysautonomia arise from changes in the peripheral autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. Cardiovascular changes, including orthostatic hypotension, supine hypertension and abnormal nocturnal blood pressure (BP), can occur in both the early and advanced stages of PD. These changes tend to increase as the disease advances. The present review aimed to describe the cognitive changes in the setting of cardiovascular dysautonomia and to discuss strategies through which these changes can be modified and managed. It is a multifactorial process usually involving decreased blood flow to the brain, resulting in the development of cerebral ischemic lesions, an increased presence of abnormal white matter signals in the brain, and a potential influence on the process of neurodegeneration in PD. Another possible explanation is this association being independent observations of PD progression. Patients with clinical symptoms of dysautonomia should undergo 24-h ambulatory BP monitoring, as they are frequently subtle and underdiagnosed.

Olfactory deficit and gastrointestinal dysfunction precede motor abnormalities in alpha-Synuclein G51D knock-in mice

Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA, which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor symptoms begin at 9 mo of age, we then sought earlier pathologies. We assessed the phosphorylation at Serine 129 of α-Syn in different tissues and detected phospho-α-Syn in the olfactory bulb and enteric nervous system at 3 mo of age. Olfactory deficit and impaired gut transit followed at 6 mo, preceding motor symptoms. The SncaG51D mice thus parallel the progression of human PD and will enable us to study PD pathogenesis and test future therapies.

Protein tyrosine phosphatase receptor type O serves as a key regulator of insulin resistance-induced α-synuclein aggregation in Parkinson’s disease

Insulin resistance (IR) was found to be a critical element in the pathogenesis of Parkinson’s disease (PD), facilitating abnormal α-synuclein (α-Syn) aggregation in neurons and thus promoting PD development. However, how IR contributes to abnormal α-Syn aggregation remains ill-defined. Here, we analyzed six PD postmortem brain transcriptome datasets to reveal module genes implicated in IR-mediated α-Syn aggregation. In addition, we induced IR in cultured dopaminergic (DA) neurons overexpressing α-Syn to identify IR-modulated differentially expressed genes (DEGs). Integrated analysis of data from PD patients and cultured neurons revealed 226 genes involved in α-Syn aggregation under IR conditions, of which 53 exhibited differential expression between PD patients and controls. Subsequently, we conducted an integrated analysis of the 53 IR-modulated genes employing transcriptome data from PD patients with different Braak stages and DA neuron subclasses with varying α-Syn aggregation scores. Protein tyrosine phosphatase receptor type O (PTPRO) was identified to be closely associated with PD progression and α-Syn aggregation. Experimental validation in a cultured PD cell model confirmed that both mRNA and protein of PTPRO were reduced under IR conditions, and the downregulation of PTPRO significantly facilitated α-Syn aggregation and cell death. Collectively, our findings identified PTPRO as a key regulator in IR-mediated α-Syn aggregation and uncovered its prospective utility as a therapeutic target in PD patients with IR.

Research Progress on the Relationship between Parkinson's Disease and REM Sleep Behavior Disorder.

An individual's quality of life is greatly affected by Parkinson's disease (PD), a prevalent neurological degenerative condition. Rapid eye movement (REM) sleep behavior disorder (RBD) is a prominent non-motor symptom commonly associated with PD. Previous studies have shown a close relationship between PD and RBD. In addition to being a prodromal symptom of PD, RBD has a major negative impact on the prognosis of PD patients. This intrinsic connection indicates that there is a bidirectional relationship between PD and RBD. This paper provides a comprehensive review of the pathological mechanism related to PD and RBD, including the α-synuclein pathological deposition, abnormal iron metabolism, neuroinflammation, glymphatic system dysfunction and dysbiosis of the gut microbiota. Increasing evidence has shown that RBD patients have the same pathogenic mechanisms that underlie PD, but relatively little research has been done on how RBD contributes to PD progression. Therefore, a more thorough investigation is warranted to characterise how RBD affects the course of PD, in order to prepare for future therapeutic trials.

Subcellular localization and function analysis of PINK1 mitron in PD progression: Mitron modulates mitochondrial morphology to regulate neuronal death

Parkinson’s disease (PD) is a multi-factorial neurodegenerative disorder. Loss or degeneration of the dopaminergic neurons in the substantia nigra and development of Lewy Bodies in dopaminergic neurons were the defining pathologic changes. MiRNAs fine-tune the protein levels by post-transcriptional gene regulation. MiR-7019-3p is encoded within the 5th intron of PD associated protein PINK1. In present study, we firstly demonstrated miR-7019-3p expression is significantly up regulated in PD mice model and neuron cell models, miR-7019-3p mainly existed in mitochondria, miR-7019-3p could regulate the structure and function of mitochondria in neuronal cells. We predicted and verified that mitochondria associated protein OPA1 and 12s rRNA, 16s rRNA and polycistronic RNA are target genes of miR-7019-3p. Finally, we proved that SP1 protein could independently regulate the expression of miR-7019-3p at the upstream. The evidences in the study suggest the role miR-7019-3p in the regulation of mitochondrial structure and function, and this kind of regulation could be implemented or promoted through the pathway of SP1-miR-7019-3p-OPA1/12s rRNA, 16s rRNA and polycistronic RNA.Our results have suggested a promising and potential therapeutic target for reversing mitochondria dysregulation in neuronal cells during Parkinson's disease process.

Long-Term Dementia Risk in Parkinson Disease.

It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point. For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years. Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.