Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons.

Synaptojanin-1 (SJ1) is a major neuronal-enriched PI(4, 5)P2 4- and 5-phosphatase implicated in the shedding of endocytic factors during endocytosis. A mutation (R258Q) that impairs selectively its 4-phosphatase activity causes Parkinsonism in humans and neurological defects in mice (SJ1RQKI mice). Studies of these mice showed, besides an abnormal assembly state of endocytic factors at synapses, the presence of dystrophic nerve terminals selectively in a subset of nigro-striatal dopamine (DA)-ergic axons, suggesting a special lability of DA neurons to the impairment of SJ1 function. Here we have further investigated the impact of SJ1 on DA neurons using iPSC-derived SJ1 KO and SJ1RQKI DA neurons and their isogenic controls. In addition to the expected enhanced clustering of endocytic factors in nerve terminals, we observed in both SJ1 mutant neuronal lines increased cilia length. Further analysis of cilia of SJ1RQDA neurons revealed abnormal accumulation of the Ca2+ channel Cav1.3 and of ubiquitin chains, suggesting a defect in the clearing of ubiquitinated proteins at the ciliary base, where a focal concentration of SJ1 was observed. We suggest that SJ1 may contribute to the control of ciliary protein dynamics in DA neurons, with implications on cilia-mediated signaling.

Generation of hiPSCs (JUCGRMi003-A) from a patient with Parkinson's disease with PARK2 mutation.

PARK2 is the most common autosomal recessive form of Parkinson's disease and is caused by mutations in parkin that result in early-onset loss of dopaminergic neurons in the substantia nigra. In this study, we established an induced pluripotent stem cell (iPSC) line from a patient harboring a homozygous exon 3 deletion in PARK2. The established iPSCs showed pluripotency, the capacity to differentiate into the three germ layers, and normal karyotypes.

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP.

Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation. The role of TPPP in Parkinsonism is often neglected in research, which we here attempt to remedy. In the normal brain, SYN and TPPP are expressed endogenously in neurons and oligodendrocytes, respectively, whilst, at an early stage of Parkinsonism, soluble hetero-associations of these proteins are found in both cell types. The cell-to-cell transmission of these proteins, which is central to disease progression, provides a unique situation for specific drug targeting. Different strategies for intervention and for the discovery of biomarkers include (i) interface targeting of the SYN-TPPP hetero-complex; (ii) proteolytic degradation of SYN and/or TPPP using the PROTAC technology; and (iii) depletion of the proteins by miRNA technology. We also discuss the potential roles of SYN and TPPP in the phenotype stabilization of neurons and oligodendrocytes.

Identification of metabolic pathways and key genes associated with atypical parkinsonism using a systems biology approach.

Atypical parkinsonism (AP) is a group of complex neurodegenerative disorders with marked clinical and pathophysiological heterogeneity. The use of systems biology tools may contribute to the characterization of hub-bottleneck genes, and the identification of its biological pathways to broaden the understanding of the bases of these disorders. A systematic search was performed on the DisGeNET database, which integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. The tools STRING 11.0 and Cytoscape 3.8.2 were used for analysis of protein-protein interaction (PPI) network. The PPI network topography analyses were performed using the CytoHubba 0.1 plugin for Cytoscape. The hub and bottleneck genes were inserted into 4 different sets on the InteractiveVenn. Additional functional enrichment analyses were performed to identify Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology for a described set of genes. The systematic search in the DisGeNET database identified 485 genes involved with Atypical Parkinsonism. Superimposing these genes, we detected a total of 31 hub-bottleneck genes. Moreover, our functional enrichment analyses demonstrated the involvement of these hub-bottleneck genes in 3 major KEGG pathways. We identified 31 highly interconnected hub-bottleneck genes through a systems biology approach, which may play a key role in the pathogenesis of atypical parkinsonism. The functional enrichment analyses showed that these genes are involved in several biological processes and pathways, such as the glial cell development, glial cell activation and cognition, pathways were related to Alzheimer disease and Parkinson disease. As a hypothesis, we highlight as possible key genes for AP the MAPT (microtubule associated protein tau), APOE (apolipoprotein E), SNCA (synuclein alpha) and APP (amyloid beta precursor protein) genes.

Practical Overview of 123I-Ioflupane Imaging in Parkinsonian Syndromes.

Parkinsonian syndromes are a heterogeneous group of progressive neurodegenerative disorders involving the nigrostriatal dopaminergic pathway and are characterized by a wide spectrum of motor and nonmotor symptoms. These syndromes are quite common and can profoundly impact the lives of patients and their families. In addition to classic Parkinson disease, parkinsonian syndromes include multiple additional disorders known collectively as Parkinson-plus syndromes or atypical parkinsonism. These are characterized by the classic parkinsonian motor symptoms with additional distinguishing clinical features. Dopamine transporter SPECT has been developed as a diagnostic tool to assess the levels of dopamine transporters in the striatum. This imaging assessment, which uses iodine 123 (123I) ioflupane, can be useful to differentiate parkinsonian syndromes caused by nigrostriatal degeneration from other clinical mimics such as essential tremor or psychogenic tremor. Dopamine transporter imaging plays a crucial role in diagnosing parkinsonian syndromes, particularly in patients who do not clearly fulfill the clinical criteria for diagnosis. Diagnostic clarification can allow early treatment in appropriate patients and avoid misdiagnosis. At present, only the qualitative interpretation of dopamine transporter SPECT is approved by the U.S. Food and Drug Administration, but quantitative interpretation is often used to supplement qualitative interpretation. The authors provide an overview of patient preparation, common imaging findings, and potential pitfalls that radiologists and nuclear medicine physicians should know when performing and interpreting dopamine transporter examinations. Alternatives to 123I-ioflupane imaging for the evaluation of nigrostriatal degeneration are also briefly discussed. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Intenzo and Colarossi in this issue.

Interhemispheric reactivity of the subthalamic nucleus sustains progressive dopamine neuron loss in asymmetrical parkinsonism.

Parkinson's disease (PD) is characterized by the progressive and asymmetrical degeneration of the nigrostriatal dopamine neurons and the unilateral presentation of the motor symptoms at onset, contralateral to the most impaired hemisphere. We previously developed a rat PD model that mimics these typical features, based on unilateral injection of a substrate inhibitor of excitatory amino acid transporters, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), in the substantia nigra (SN). Here, we used this progressive model in a multilevel study (behavioral testing, in vivo 1H-magnetic resonance spectroscopy, slice electrophysiology, immunocytochemistry and in situ hybridization) to characterize the functional changes occurring in the cortico-basal ganglia-cortical network in an evolving asymmetrical neurodegeneration context and their possible contribution to the cell death progression. We focused on the corticostriatal input and the subthalamic nucleus (STN), two glutamate components with major implications in PD pathophysiology. In the striatum, glutamate and glutamine levels increased from presymptomatic stages in the PDC-injected hemisphere only, which also showed enhanced glutamatergic transmission and loss of plasticity at corticostriatal synapses assessed at symptomatic stage. Surprisingly, the contralateral STN showed earlier and stronger reactivity than the ipsilateral side (increased intraneuronal cytochrome oxidase subunit I mRNA levels; enhanced glutamate and glutamine concentrations). Moreover, its lesion at early presymptomatic stage halted the ongoing neurodegeneration in the PDC-injected SN and prevented the expression of motor asymmetry. These findings reveal the existence of endogenous interhemispheric processes linking the primary injured SN and the contralateral STN that could sustain progressive dopamine neuron loss, opening new perspectives for disease-modifying treatment of PD.

Proteomic analysis of X-linked dystonia parkinsonism disease striatal neurons reveals altered RNA metabolism and splicing.

X-linked dystonia-parkinsonism (XDP) is a rare neurodegenerative disease endemic to the Philippines. The genetic cause for XDP is an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within intron 32 of TATA-binding protein associated factor 1 (TAF1) that causes an alteration of TAF1 splicing, partial intron retention, and decreased transcription. Although TAF1 is expressed in all organs, medium spiny neurons (MSNs) within the striatum are one of the cell types most affected in XDP. To define how mutations in the TAF1 gene lead to MSN vulnerability, we carried out a proteomic analysis of human XDP patient-derived neural stem cells (NSCs) and MSNs derived from induced pluripotent stem cells. NSCs and MSNs were grown in parallel and subjected to quantitative proteomic analysis in data-independent acquisition mode on the Orbitrap Eclipse Tribrid mass spectrometer. Subsequent functional enrichment analysis demonstrated that neurodegenerative disease-related pathways, such as Huntington's disease, spinocerebellar ataxia, cellular senescence, mitochondrial function and RNA binding metabolism, were highly represented. We used weighted coexpression network analysis (WGCNA) of the NSC and MSN proteomic data set to uncover disease-driving network modules. Three of the modules significantly correlated with XDP genotype when compared to the non-affected control and were enriched for DNA helicase and nuclear chromatin assembly, mitochondrial disassembly, RNA location and mRNA processing. Consistent with aberrant mRNA processing, we found splicing and intron retention of TAF1 intron 32 in XDP MSN. We also identified TAF1 as one of the top enriched transcription factors, along with YY1, ATF2, USF1 and MYC. Notably, YY1 has been implicated in genetic forms of dystonia. Overall, our proteomic data set constitutes a valuable resource to understand mechanisms relevant to TAF1 dysregulation and to identify new therapeutic targets for XDP.

A Complex Interplay of DJ-1, LRRK2, and Nrf2 in the Regulation of Mitochondrial Function in Cypermethrin-Induced Parkinsonism.

Cypermethrin impairs mitochondrial function, induces redox imbalance, and leads to Parkinsonism in experimental animals. Knockdown of deglycase-1 (DJ-1) gene, which encodes a redox-sensitive antioxidant protein, aggravates cypermethrin-mediated α-synuclein overexpression and oxidative alteration of proteins. DJ-1 is also reported to be essential for maintaining stability of nuclear factor erythroid 2-related factor 2 (Nrf2), shielding cells against oxidative insult. Leucine-rich repeat kinase 2 (LRRK2), another protein associated with Parkinson's disease, is also involved in regulating mitochondrial function. However, underlying molecular mechanisms remain elusive. The study intended to explore an interaction of DJ-1, LRRK2, and Nrf2 in the regulation of mitochondrial function in cypermethrin-induced Parkinsonism. Small interfering RNA-mediated knockdown of DJ-1 and LRRK2 gene and pharmacological activation of Nrf2 were performed in rats and/or human neuroblastoma cells with or without cypermethrin. Indexes of oxidative stress, mitochondrial impairment, and Parkinsonism along with α-synuclein expression, post-translational modification, and aggregation were measured. DJ-1 gene knockdown exacerbated cypermethrin-induced increase in oxidative stress and intrinsic apoptosis and reduction in expression of mitochondrial antioxidant proteins via inhibiting nuclear translocation of Nrf2. Additionally, cypermethrin-induced oxidative stress, mitochondrial impairment, and α-synuclein expression and aggregation were found to be suppressed by LRRK2 gene knockdown, by promoting Nrf2 nuclear translocation and expression of mitochondrial antioxidant proteins. Furthermore, Nrf2 activator, sulforaphane, ameliorated cypermethrin-induced mitochondrial impairment and oxidative stress and provided protection against dopaminergic neuronal death. The findings indicate that DJ-1 and LRRK2 independently alter Nrf2-mediated changes and a complex interplay among DJ-1, LRRK2, and Nrf2 exists in the regulation of mitochondrial function in cypermethrin-induced Parkinsonism.

Addition of α-synuclein aggregates to the intestinal environment recapitulates Parkinsonian symptoms in model systems.

The gut-brain axis plays a vital role in Parkinson's disease (PD). The mechanisms of gut-brain transmission mainly focus on α-synuclein deposition, intestinal inflammation and microbiota function. A few studies have shown the trigger of PD pathology in the gut. α-Synuclein is highly conserved in food products, which was able to form ß-folded aggregates and to infect the intestinal mucosa. In this study we investigated whether α-synuclein-preformed fibril (PFF) exposure could modulate the intestinal environment and induce rodent models replicating PD pathology. We first showed that PFF could be internalized into co-cultured Caco-2/HT29/Raji b cells in vitro. Furthermore, we demonstrated that PFF perfusion caused the intestinal inflammation and activation of enteric glial cells in an ex vivo intestinal organ culture and in an in vivo intestinal mouse coloclysis model. Moreover, we found that PFF exposure through regular coloclysis induced PD pathology in wild-type (WT) and A53T α-synuclein transgenic mice with various phenotypes. Particularly in A53T mice, PFF induced significant behavioral disorders, intestinal inflammation, α-synuclein deposition, microbiota dysbiosis, glial activation as well as degeneration of dopaminergic neurons in the substantia nigra. In WT mice, however, the PFF induced only mild behavioral abnormalities, intestinal inflammation, α-synuclein deposition, and glial activation, without significant changes in microbiota and dopaminergic neurons. Our results reveal the possibility of α-synuclein aggregates binding to the intestinal mucosa and modeling PD in mice. This study may shed light on the investigation and early intervention of the gut-origin hypothesis in neurodegenerative diseases.

Nanocarrier Mediated Intranasal Drug Delivery Systems for the Management of Parkinsonism: A Review.

The transport of drugs to the brain becomes a key concern when treating disorders of the central nervous system. Parkinsonism is one of the major concerns across the world populations, which causes difficulty in coordination and balance. However, the blood-brain barrier is a significant barrier to achieving optimal brain concentration through oral, transdermal, and intravenous routes of administration. The intranasal route with nanocarrier-based formulations has shown potential for managing Parkinsonism disorder (PD). Direct delivery to the brain through the intranasal route is possible via the olfactory and trigeminal pathways using drug-loaded nanotechnology-based drug delivery systems. The critical analysis of reported works demonstrates dose reduction, brain targeting, safety, effectiveness, and stability for drug-loaded nanocarriers. The important aspects of intranasal drug delivery, PD details, and nanocarrier-based intranasal formulations in PD management with a discussion of physicochemical characteristics, cell line studies, and animal studies are the major topics in this review. Patent reports and clinical investigations are summarized in the last sections.

Icariin attenuates dopaminergic neural loss in haloperidol-induced Parkinsonism in rats via GSK-3ß and tyrosine hydroxylase regulation mechanism.

Parkinson's Disease (PD) is an age-dependent, incessant, dynamic neurodegenerative illness. In animal models, the administration of the dopaminergic D2 antagonist Haloperidol (HP) affects the nigrostriatal pathway, inducing catalepsy, a state of immobility like PD, bradykinesia, and akinesia. The present study investigated the neural effects of Icariin (ICA), a flavonoid derived from Herba Epimedii, against HP-induced PD in rats compared to a standard drug levodopa (L-DOPA). Twenty-four adult male rats were divided into 4 groups: the control group treated with vehicle, the 2nd group treated with HP intraperitoneally, the 3rd group treated with the same dose of HP+L-DOPA orally, and the 4th one, treated with the same dose of HP+ICA orally. All the groups were treated for fourteen consecutive days. Two days before the last dose, locomotor activity was assessed in open field and rotarod tasks. At the end of the experiment, the malondialdehyde, nitric oxide (NO), iron, glycogen synthase kinase-3beta (GSK-3ß), and tyrosine hydroxylase (TH) contents, glutathione S-transferase, catalase, superoxide dismutase, activities were estimated in the midbrain. Also, cortex and midbrain monoamine contents (norepinephrine, dopamine, and serotonin) were determined. Moreover, the midbrain histopathology was detected in all treated groups. The results suggested that the neuroleptic effect of HP was completely improved by ICA. This improvement occurred by decreasing the neurotoxicity via lowering midbrain lipid peroxidation, NO, GSK-3ß contents, increasing antioxidant biomarkers, TH, and recovering the treated groups' cortex and midbrain monoamines contents. In conclusion, this study suggests that ICA is a suitable treatment for Parkinson's induced by HP.

Transcranial direct current stimulation of the prefrontal cortex improves depression-like behaviors in rats with Parkinson's disease.

Depression associated with Parkinson's disease (PD) seriously affects patients, and there is a lack of effective treatments. Transcranial direct current stimulation (tDCS) is increasingly used as a new non-invasive neuromodulation technique in the treatment of neuropsychiatric diseases. However, there is a paucity of research on tDCS for PD-related depression. Our study used PD model rats established with unilateral destruction of the medial forebrain bundle (MFB) to observe the modulatory effects of tDCS acting on the mPFC on depression-like behaviors. We found that tDCS acting on the mPFC improved depression-like behaviors in PD model rats by increasing sucrose intake in sucrose preference test (n = 7-10 rats/group) and shortening immobility time in forced swimming test (n = 7-8 rats/group). Meanwhile, tDCS decreased the expression of c-Fos protein (n = 8-11 rats/group) and the excitation of glutamatergic neurons (n = 6-8 rats/group) in the PrL and LHb of PD model rats. Western blots showed that tDCS decreased the overexpression of serine 845 phosphorylation site of AMPA receptor GluR1 (p-GluR1-S845) in the PrL and LHb of PD model rats (n = 8-11 rats/group), and the overexpression of p-GluR1-S831 in the LHb (n = 8-11 rats/group). The results of this study show that tDCS acting on the mPFC helps to improve PD-related depression, which involves the modulation of excitability and AMPA receptor phosphorylation on the PrL and LHb neurons.

A primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson's disease.

The degenerative process in Parkinson's disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.

Neuroprotective effects of isatin and afobazole in rats with rotenone-induced Parkinsonism are accompanied by increased brain levels of Triton X-100 soluble alpha-synuclein.

Effects of the endogenous neuroprotector isatin and the pharmacological drug afobazole (exhibiting neuroprotective properties) on behavioral reactions and quantitative changes in the brain proteomic profile have been investigated in rats with experimental rotenone Parkinsonism. A single dose of isatin (100 mg/kg subcutaneously on the last day of a 7-day course of rotenone administration) improved the motor activity of rats with rotenone-induced Parkinsonism in the open field test (horizontal movements) and the rotating rod test. Afobazole (10 mg/kg intraperitoneally, daily during the 7-day course of rotenone administration) reduced the manifestations of rigidity and postural instability. Proteomic analysis, performed using brain samples obtained the day after the last administration of rotenone and neuroprotectors, revealed similar quantitative changes in the brain of rats with rotenone Parkinsonism. An increase in the relative content of 65 proteins and a decrease in the relative content of 21 proteins were detected. The most pronounced changes - an almost ninety-fold increase in the alpha-synuclein content - were found in the brains of rats treated with isatin. In animals of the experimental groups treated with "Rotenone + Isatin", as well as "Rotenone + Afobazole", the increase in the relative content of this protein in the brain was almost 60 and 50 times higher than the control values. Taking into consideration the known data on the physiological role of alpha-synuclein, an increase in the content of this protein in the brain upon administration of neuroprotectors to animals with rotenone Parkinsonism may represent a compensatory reaction, at least in the early stages of this disease and the beginning of its treatment.

[The clinical application value of brain 18F-FDG PET/CT in the diagnostics of Parkinsonian syndromes].

Objective: To analyze the PET/CT imaging features of fluoride 18F-fluorodeoxyglucose (18F-FDG) in patients with various types of Parkinson's syndrome (PS), and to establish a "diagnostic tree" model of 18F-FDG PET/CT for PS. Methods: Data of patients with Parkinson's disease (PD), patients with multiple system atrophy cerebellar type (MSA-C), and patients with multiple system atrophy Parkinson's type (MSA-P)admitted to the Neurology Department of Huashan Hospital affiliated to Fudan University from January 2019 to December 2021. 18F-FDG PET/CT examination was conducted in all patients. Clinical and follow-up data was collected to determine clinical diagnosis. The specific patterns of brain glucose metabolism in patients with various types of Parkinsonism were observed and their utility in the differential diagnosis of the disease was analyzed. 18F-FDG PET/CT imaging"diagnostic tree"model was established and its value in the differential diagnosis of Parkinsonism was verified. Results: A total of 320 patients, 187 males and 133 females, aged (62±9) years, were enrolled in our study, including 80 PD, 90 PSP, 114 MSA-C and 36 MSA-P patients. The differential diagnostic features of cerebral glucose metabolism of Parkinsonism were as follows: the metabolism of putamen increased in PD patients, the metabolism of caudate nucleus, thalamus, midbrain, and frontal lobe decreased in PSP patients, the metabolism of cerebellum decreased in MSA-C patients, and the metabolism of putamen and cerebellum decreased in MSA-P patients. The sensitivity and specificity of the"diagnostic tree"model are 88.75% and 91.25% for PD diagnosis, 54.44% and 96.96% for PSP diagnosis, 87.72% and 86.41% for MSA-C diagnosis, and 55.56% and 91.55% for MSA-P diagnosis, respectively. It could correctly classify 75%(240/320) of patients. Conclusions: Characteristic metabolism patterns of brain in 18F-FDG PET/CT imaging is significant for the differential diagnosis of PD, PSP, MSA-C and MSA-P. The"diagnostic tree"model is valuable for clinical diagnosis.

Activation of mGlu2/3 receptors in the striatum alleviates L-DOPA-induced dyskinesia and inhibits abnormal postsynaptic molecular expression.

Group II metabotropic glutamate receptors (mGlu2/3 receptors) have been regarded as promising candidates for the treatment of L-DOPA-induced dyskinesia (LID); however, confirmation is still lacking. As the hub of the basal ganglia circuit, the striatum plays a critical role in action control. Supersensitive responsiveness of glutamatergic corticostriatal input may be the key mechanism for the development of LID. In this study, we first examined the potency of LY354740 (12 mg/kg, i.p.) in modulating glutamate and dopamine release in lesioned striatum of stable LID rats. Then, we injected LY354740 (20nmoL or 40nmoL in 4 µL of sterile 0.9 % saline) directly into the lesioned striatum to verify its ability to reduce or attenuate L-DOPA-induced abnormal involuntary movements. In experiment conducted in established LID rats, after continuous injection for 4 days, we found that LY354740 significantly reduced the expression of dyskinesia. In another experiment conducted in parkinsonism rat models, we found that LY354740 attenuated the development of LID with an inverted-U dose-response curve. The role of LY354740 in modulating striatal expressions of LID-related molecular changes was also assessed after these behavioral experiments. We found that LY354740 significantly inhibited abnormal expressions of p-Fyn/p-NMDA/p-ERK1/2/p-HistoneH3/ΔFosB, which is in line with its ability to alleviate abnormal involuntary movements in both LID expression and induction phase. Our study indicates that activation of striatal mGlu2/3 receptors can attenuate the development of dyskinesia in parkinsonism rats and provide some functional improvements in LID rats by inhibiting LID-related molecular changes.

Brainstem Modulates Parkinsonism-Induced Orofacial Sensorimotor Dysfunctions.

Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated.

Inhibition of ACSL4 Alleviates Parkinsonism Phenotypes by Reduction of Lipid Reactive Oxygen Species.

Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be defined. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies polyunsaturated fatty acids (PUFAs) which is essential to trigger ferroptosis, and is suggested as a key gene in the pathogenesis of several neurological diseases including ischemic stroke and multiple sclerosis. Here, we report that ACSL4 expression in the substantia nigra (SN) was increased in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated model of PD and in dopaminergic neurons in PD patients. Knockdown of ACSL4 in the SN protected against dopaminergic neuronal death and motor deficits in the MPTP mice, while inhibition of ACSL4 activity with Triacsin C similarly ameliorated the parkinsonism phenotypes. Similar effects of ACSL4 reduction were observed in cells treated with 1-methyl-4-phenylpyridinium (MPP+) and it specifically prevented the lipid ROS elevation without affecting the mitochondrial ROS changes. These data support ACSL4 as a therapeutic target associated with lipid peroxidation in PD.

Validation of the REM behaviour disorder phenoconversion-related pattern in an independent cohort.

BACKGROUND: A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients. METHODS: Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [18F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power. RESULTS: The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18-15.39). CONCLUSIONS: The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials.

Betanin improves motor function and alleviates experimental Parkinsonism via downregulation of TLR4/MyD88/NF-κB pathway: Molecular docking and biological investigations.

Parkinson's disease (PD) is a progressive neuroinflammatory and degenerative disease. In this study, we investigated the neuroprotective action of betanin in the rotenone-induced Parkinson-like mice model. Twenty-eight adult male Swiss albino mice were divided into four groups: Vehicle, Rotenone, Rotenone + Betanin 50 mg/kg, and Rotenone + Betanin 100 mg/kg. Parkinsonism was induced by subcutaneous injection of 9 doses of rotenone (1 mg/kg/48 h) plus betanin at 50 and 100 mg/kg/48 h in rotenone + betanin groups for twenty days. Motor dysfunction was assessed after the end of the therapeutic period using the pole, rotarod, open-field, grid, and cylinder tests. Malondialdehyde, reduced glutathione (GSH), Toll-like receptor 4 (TLR4), myeloid differentiation primary response-88 (MyD88), nuclear factor kappa- B (NF-κB), neuronal degeneration in the striatum were evaluated. In addition, we assessed the immunohistochemical densities of tyrosine hydroxylase (TH) in Str and in substantia nigra compacta (SNpc). Our results showed that rotenone remarkably decreased (results of tests), increased decreased TH density with a significant increase in MDA, TLR4, MyD88, NF-κB, and a decrease in GSH (p < 0.05). Treatment with betanin significantly results of tests), increased TH density. Furthermore, betanin significantly downregulated malondialdehyde and improved GSH. Additionally, the expression of TLR4, MyD88, and NF-κB was significantly alleviated. Betanin's powerful antioxidative and anti-inflammatory properties can be related to its neuroprotective potential as well as its ability to delay or prevent neurodegeneration in PD.