Parkinson's Disease Substantia Nigra Research Articles

Single-Cell Nuclear Sequencing Atlas Revealed the Induction of Parkinson's Disease by RELN+ Neuron 3 and the Gene Regulatory Network of MSRA.

To determine the cell types that promoted the progression of Parkinson's disease (PD) using the substantia nigra in the brain tissues derived from patients with PD and normal controls. PD is an incurable neurodegenerative disease that threatens the physical activity of the aging population, and the complex molecular mechanisms remain be comprehensively elucidated. To describe potential disease-promoting cell types in PD and to provide a theoretical basis. Single-cell nuclear sequencing data of nine PD samples and control samples from Gene Expression Omnibus (GEO) were included, and heterogeneous cell subpopulations in the substantia nigra were identified by annotation analysis. Potential pathogenic cell subpopulations of PD were determined based on the expression data of marker genes. Cell differentiation trajectories and communication networks were generated by Pseudotime trajectory analysis and cell communication analysis. Furthermore, single-- cell regulatory network inference and clustering (SCENIC) analysis was conducted to determine the regulatory network of transcription factor-target genes in PD. Among the nine cell subpopulations classified, RELN+neuron 3 showed reduced abundance and dopamine secretion capacity in PD and was therefore considered as a promoter of PD pathogenesis and progression. The regulatory network of MSRA action was involved in the developmental process of cells in the central nervous system, indicating that MSRA and its targets might serve as potential therapeutic targets for PD. RELN+neuron 3 had two directions of differentiation, specifically, branch 1 exhibited a high apoptotic profile and branch 2 exhibited a high cell death profile. In addition, the intensity of EPHA and EPHB signaling was attenuated between RELN+neuron 3 and other cell subpopulations. To conclude, this study identified a subpopulation of RELN+neuron 3 cells with markedly reduced abundance in the brain substantia nigra in PD. The MSRA-involved gene regulatory networks was considered as a novel therapeutic network for PD.

Mitochondrial iron dyshomeostasis and its potential as a therapeutic target for Parkinson's disease

Abnormal iron accumulation has been implicated in the etiology of Parkinson's disease (PD). Understanding how iron damages dopaminergic neurons in the substantia nigra (SN) of PD is particularly important for developing targeted neurotherapeutic strategies for the disease. However, it is still not fully understood how excess iron contributes to the neurodegeneration of dopaminergic neurons in PD. There has been increased attention on mitochondrial iron dyshomeostasis, iron-induced mitochondrial dysfunction and ferroptosis in PD. Therefore, this review begins with a brief introduction to describe cellular iron metabolism and the dysregulation of iron metabolism in PD. Then we provide an update on how iron is delivered to mitochondria and induces the damage of dopaminergic neurons in PD. In addition, we also summarize new research progress on iron-dependent ferroptosis in PD and mitochondria-localized proteins involved in ferroptosis. This will provide new insight into potential therapeutic strategies targeting mitochondrial iron dysfunction.

Recipient Reaction and Composition of Autologous Sural Nerve Tissue Grafts into the Human Brain.

Parkinson's disease (PD) is a severe neurological disease for which there is no effective treatment or cure, and therefore it remains an unmet need in medicine. We present data from four participants who received autologous transplantation of small pieces of sural nerve tissue into either the basal forebrain containing the nucleus basalis of Meynert (NBM) or the midbrain substantia nigra (SN). The grafts did not exhibit significant cell death or severe host-tissue reaction up to 55 months post-grafting and contained peripheral cells. Dopaminergic neurites showed active growth in the graft area and into the graft in the SN graft, and cholinergic neurites were abundant near the graft in the NBM. These results provide a histological basis for changes in clinical features after autologous peripheral nerve tissue grafting into the NBM or SN in PD.

Identification of Cuproptosis Clusters and Integrative Analyses in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease; it mainly occurs in the elderly population. Cuproptosis is a newly discovered form of regulated cell death involved in the progression of various diseases. Combining multiple GEO datasets, we analyzed the expression profile and immunity of cuproptosis-related genes (CRGs) in PD. Dysregulated CRGs and differential immune responses were identified between PD and non-PD substantia nigra. Two CRG clusters were defined in PD. Immune analysis suggested that CRG cluster 1 was characterized by a high immune response. The enrichment analysis showed that CRG cluster 1 was significantly enriched in immune activation pathways, such as the Notch pathway and the JAK-STAT pathway. KIAA0319, AGTR1, and SLC18A2 were selected as core genes based on the LASSO analysis. We built a nomogram that can predict the occurrence of PD based on the core genes. Further analysis found that the core genes were significantly correlated with tyrosine hydroxylase activity. This study systematically evaluated the relationship between cuproptosis and PD and established a predictive model for assessing the risk of cuproptosis subtypes and the outcome of PD patients. This study provides a new understanding of PD-related molecular mechanisms and provides new insights into the treatment of PD.

Genetic impacts on nigral iron deposition in Parkinson's disease: A preliminary quantitative susceptibility mapping study.

Dysfunction of iron metabolism, especially in substantia nigra (SN), is widely acknowledged in Parkinson's disease (PD), but the genetic influence on iron deposition remains largely unknown. Thus, in this study, we aimed to investigate potential genetic impacts on iron deposition in PD. Seventy-four subjects, including 38 patients with PD and 36 age-matched normal controls, participated in this study. Imaging genetic association analysis was used to identify the specific influence of single nucleotide polymorphism (SNP) on iron-related quantitative traits (QT). Genetic effects on iron deposition at the disease level, SNP level, and their interactive effect were highlighted. Four strong SNP-QT associations were detected: rs602201-susceptibility of bilateral SN, rs198440-susceptibility of left SN, and rs7895403-susceptibility of left caudate head. Detailed analyses showed that: (1) significant iron deposition was exclusively found in bilateral SN in PD; (2) altered polymorphisms of the A allele/A- genotype of rs602201 and G allele/G- genotype of rs198440 and rs7895403 were more frequently observed in PD; (3) for rs602201, among all subjects, A- genotype carriers showed significantly increased iron content than TT genotype in bilateral SN; for rs198440 and rs7895403, G- carriers showed increased iron content than AA genotype in left SN and left caudate head, respectively; and (4) rs602201 exhibited significant SNP-by-disease interaction in bilateral SN. This study shows that rs602201 and rs198440 have a stimulative impact on nigral iron deposition in PD, which provides improved understanding of iron-related pathogenesis in PD, and specifically, that vulnerability to iron deposition in SN is genetic-based.

DNA Methylation of α-Synuclein Intron 1 Is Significantly Decreased in the Frontal Cortex of Parkinson's Individuals with GBA1 Mutations.

Parkinson's disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7-10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-GBA1 are incompletely understood, but, as in idiopathic PD, α-synuclein accumulation is thought to play a key role. It has been hypothesized that this overexpression of α-synuclein is caused by epigenetic modifications. In this paper, we analyze DNA methylation levels at 17 CpG sites located within intron 1 and the promoter of the α-synuclein (SNCA) gene in three different brain regions (frontal cortex, putamen and substantia nigra) in idiopathic PD, PD-GBA1 and elderly non-PD controls. In all three brain regions we find a tendency towards a decrease in DNA methylation within an eight CpG region of intron 1 in both idiopathic PD and PD-GBA1. The trend towards a reduction in DNA methylation was more pronounced in PD-GBA1, with a significant decrease in the frontal cortex. This suggests that PD-GBA1 and idiopathic PD have distinct epigenetic profiles, and highlights the importance of separating idiopathic PD and PD-GBA1 cases. This work also provides initial evidence that different genetic subtypes might exist within PD, each characterized by its own pathological mechanism. This may have important implications for how PD is diagnosed and treated.

Application value of multiparametric MRI for evaluating iron deposition in the substantia nigra in Parkinson's disease.

This study aimed to investigate the application value of multi-parametric magnetic resonance imaging (MRI) in the diagnosis of iron deposition in the substantia nigra dense zone in Parkinson's disease (PD) and to evaluate the diagnostic value of the correlation among multi-parametric imaging indicators, clinical stage, and disease duration. Thirty-six patients with clinically confirmed PD and 36 healthy controls were enrolled. The disease course was recorded, and PD severity was graded using the Hoehn-Yahr (H-Y) scale. All subjects underwent magnetic sensitivity weighted imaging (SWI), neuromelanin magnetic resonance imaging (NM-MRI), and a T2*mapping sequence. Based on the fusion of the NM-MRI and SWI amplitude maps, phase maps, and T2*MAPPING value maps, NM-MRI was used to delineate the dense zone of the substantia nigra, which was divided into three sub-regions: upper, middle, and lower. In this way, the amplitude, phase, and R2* values of each sub-region and the average value of the sum of the three sub-regions were obtained simultaneously in the SWI amplitude, phase, and T2*MAPPING maps. The multi-parameter imaging indices were compared between the two groups, and the correlation between them and clinical indices was evaluated in the PD group. The upper (amplitude, phase value, R2* value), middle, and lower (amplitude) right substantia nigra compact zones were significantly different between the PD and control groups. The upper (phase value, R2* value) and middle (amplitude) areas of the left substantia nigra compact zone were also significantly different between the two groups (all P < 0.05). The mean values (amplitude, phase value, R2* value) of the right substantia nigra densification zone and the mean values (phase value) of the left substantia nigra densification zone were also significantly different (all P < 0.05). Amplitudes in the middle and lower parts of the right substantia nigra dense zone were negatively correlated with the H-Y grade (middle: r = -0.475, P = 0.003; lower: r = -0.331, P = 0.049). Amplitudes of the middle and lower parts of the dense zone of the left substantia nigra were negatively correlated with the H-Y grade (middle: r = -0.342, P = 0.041; lower: r = -0.399, P = 0.016). The average amplitude of the right substantia nigra compact zone was negatively correlated with the H-Y grade (r = -0.367, P = 0.027). The average R2* value of the compact zone of the left substantia nigra was positively correlated with the H-Y grade (r = 0.345, P = 0.040). Multiparametric MRI sequence examination has application value in the evaluation of iron deposition in the dense zone of the substantia nigra in PD. Combined with NM-MRI, fusion analysis is beneficial for accurately locating the substantia nigra compact zone and quantitatively analyzing the iron deposition in different sub-regions. Quantitative iron deposition in the middle and lower parts of the substantia nigra dense zone may become an imaging biological indicator for early diagnosis, severity evaluation, and follow-up evaluation of PD and is thus conducive for clinical diagnosis and treatment evaluation.

Potential Biomarkers for Parkinson Disease from Functional Enrichment and Bioinformatic Analysis of Global Gene Expression Patterns of Blood and Substantia Nigra Tissues.

The Parkinson disease (PD) is the second most common neurodegenerative disorder affecting the central nervous system and motor functions. The biological complexity of PD is yet to reveal potential targets for intervention or to slow the disease severity. Therefore, this study aimed to compare the fidelity of blood to substantia nigra (SN) tissue gene expression from PD patients to provide a systematic approach to predict role of the key genes of PD pathobiology. Differentially expressed genes (DEGs) from multiple microarray data sets of PD blood and SN tissue from GEO database are identified. Using the theoretical network approach and variety of bioinformatic tools, we prioritized the key genes from DEGs. A total of 540 and 1024 DEGs were identified in blood and SN tissue samples, respectively. Functional pathways closely related to PD such as ERK1 and ERK2 cascades, mitogen-activated protein kinase (MAPK) signaling, Wnt, nuclear factor-κB (NF-κB), and PI3K-Akt signaling were observed by enrichment analysis. Expression patterns of 13 DEGs were similar in both blood and SN tissues. Comprehensive network topological analysis and gene regulatory networks identified additional 10 DEGs functionally connected with molecular mechanisms of PD through the mammalian target of rapamycin (mTOR), autophagy, and AMP-activated protein kinase (AMPK) signaling pathways. Potential drug molecules were identified by chemical-protein network and drug prediction analysis. These potential candidates can be further validated in vitro/in vivo to be used as biomarkers and/or novel drug targets for the PD pathology and/or to arrest or delay the neurodegeneration over the years, respectively.

7-T Neuromelanin and R2* MRI in Parkinson Disease.

HomeRadiologyVol. 305, No. 2 PreviousNext Reviews and CommentaryFree AccessImages in Radiology7-T Neuromelanin and R2* MRI in Parkinson DiseaseDhairya A. Lakhani, Erik H. Middlebrooks Dhairya A. Lakhani, Erik H. Middlebrooks Author AffiliationsFrom the Department of Radiology, West Virginia University, Morgantown, W.Va. (D.A.L.); and Department of Radiology, Mayo Clinic College of Medicine and Science, 4500 San Pablo Rd, Jacksonville, FL 32224 (E.H.M.).Address correspondence to E.H.M. (email: [email protected]).Dhairya A. LakhaniErik H. Middlebrooks Published Online:Aug 2 2022https://doi.org/10.1148/radiol.220230MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In A 76-year-old man presented with worsening balance, shuffling gait, and right-hand tremor, beginning 3 years before evaluation. On examination, he had reduced facial expressions, reduced blink rate, and hypophonic voice. His gait was slow and shuffling, with bilateral reduced arm swing. He also had rigidity and bradykinesia in all four extremities, greater on the right. His examination features were typical of the akinetic-rigid subtype of Parkinson disease (PD). He underwent brain MRI to support the diagnosis and to assess for other etiologies, such as an atypical parkinsonian syndrome.In this case, we used a high-spatial-resolution multiecho gradient-echo sequence with magnetization transfer pulse at 7 T to image neuromelanin in the substantia nigra, which normally has a high concentration of neuromelanin-rich cells. Neuromelanin imaging stands to benefit from 7-T MRI due to higher signal-to-noise ratio, tissue contrast, and spatial resolution. Reduced size and signal intensity of the substantia nigra were consistent with PD (Figure). Additionally, the multiecho sequence allowed for the quantification of the R2*, which reveals elevated iron deposition in this case, another histopathologic feature of PD (Figure). The combination of both biomarkers has potential to be a powerful tool for diagnosis and monitoring progression of PD.Images in a 76-year-old man with akinetic-rigid subtype Parkinson disease (PD) with symptoms greater on the right side. (A) Axial neuromelanin-sensitive MRI scan derived from rigid subtype PD shows reduced size and signal intensity of the substantia nigra (SN) (arrows) on the first echo image of a neuromelanin-sensitive three-dimensional multiecho fast low-angle shot, or FLASH, MRI scan with magnetization transfer pulse (7-T Siemens MAGNETOM Terra [Siemens Healthineers]; repetition time, 52 m/sec; echo time, 2.18, 4.15, and 7.09 m/sec; section thickness, 1.5 mm; flip angle, 16°; averages, 1; interpolated voxel size, 0.4 × 0.4 × 1.5 mm; acquisition time, 10 minutes and19 seconds). (B) MRI scan in a 73-year-old woman with the diagnosis of essential tremor is shown for illustration of the normal appearance of the substantia nigra (arrows) as comparison. (C) Plot graph of the substantia-nigra signal intensity (normalized by the adjacent cerebral-peduncle signal intensity) over the three echoes shows decreased neuromelanin in the patient with PD (greater decrease in the left substantia nigra) on the first echo neuromelanin-sensitive image. There is also a more rapid decrease in signal intensity over the second and third echoes, reflecting increased R2* effect from elevated iron deposition.Download as PowerPointOpen in Image Viewer Disclosures of conflicts of interest: D.A.L. No relevant relationships. E.H.M. Clinical trial and research funding paid to institution by Varian Medical Systems and Boston Scientific; unrelated consultant fees from Boston Scientific.Article HistoryReceived: Feb 1 2022Revision requested: Mar 7 2022Revision received: Mar 15 2022Accepted: Mar 18 2022Published online: Aug 02 2022Published in print: Nov 2022 FiguresReferencesRelatedDetailsRecommended Articles Substantia Nigra Volumetry with 3-T MRI in De Novo and Advanced Parkinson DiseaseRadiology2020Volume: 296Issue: 2pp. 401-410Differential Effect of Iron and Myelin on Susceptibility MRI in the Substantia NigraRadiology2021Volume: 301Issue: 3pp. 682-691High-Spatial-Resolution Diffusion MRI in Parkinson Disease: Lateral Asymmetry of the Substantia NigraRadiology2019Volume: 291Issue: 1pp. 149-157Imaging the Substantia Nigra in Parkinson Disease and Other Parkinsonian SyndromesRadiology2021Volume: 300Issue: 2pp. 260-278Is High-Spatial-Resolution Diffusion MRI Applicable for the Diagnosis of Parkinson Disease?Radiology2019Volume: 292Issue: 1pp. 267-268See More RSNA Education Exhibits Parkinsonian Syndromes: The Past, Present, and FutureDigital Posters2019Contemporary MRI Imaging in Parkinson's DiseaseDigital Posters2019The Role of MR-guided Focused Ultrasound as a Symptomatic Treatment for Parkinson's Disease: Behind and BeyondDigital Posters2020 RSNA Case Collection Primary HemochromatosisRSNA Case Collection2021NeuroferritinopathyRSNA Case Collection2021Multiple System Atrophy (MSA)RSNA Case Collection2021 Vol. 305, No. 2 Metrics Altmetric Score PDF download

Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein.

SUMMARYα-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson’s disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.

Imaging the Substantia Nigra in Parkinson Disease and Other Parkinsonian Syndromes.

Parkinson disease is characterized by dopaminergic cell loss in the substantia nigra of the midbrain. There are various imaging markers for Parkinson disease. Recent advances in MRI have enabled elucidation of the underlying pathophysiologic changes in the nigral structure. This has contributed to accurate and early diagnosis and has improved disease progression monitoring. This article aims to review recent developments in nigral imaging for Parkinson disease and other parkinsonian syndromes, including nigrosome imaging, neuromelanin imaging, quantitative iron mapping, and diffusion-tensor imaging. In particular, this article examines nigrosome imaging using 7-T MRI and 3-T susceptibility-weighted imaging. Finally, this article discusses volumetry and its clinical importance related to symptom manifestation. This review will improve understanding of recent advancements in nigral imaging of Parkinson disease. Published under a CC BY 4.0 license.

Automated segmentation of substantia nigra and red nucleus using quantitative susceptibility mapping images: Application to Parkinson's disease

Accurate segmentation of substantia nigra (SN) and red nucleus (RN) is challenging, yet important for understanding health problems like Parkinson's disease (PD). This paper proposes an algorithm to segment SN and RN from quantitative susceptibility mapping (QSM) MRI and use the results to investigate PD. Algorithm-derived segments (based on level set and watershed transform) are compared to expert manually-derived segmentations in 40 participants. Using Bayesian regression models, we compare QSM values between PD and control groups, and investigate relationships with global cognitive ability and motor severity in PD. The proposed algorithm produces high quality segmentations, validated against expert manual segmentation. We show moderate evidence of increased QSM values in SN in PD relative to controls, with moderate evidence for association between QSM, global cognitive ability, and motor impairment in the SN in PD. We suggest an improved midbrain segmentation algorithm may be useful for monitoring iron-related disease severity in Parkinson's.

Patterns of diffusion kurtosis changes in Parkinson's disease subtypes

BackgroundDiffusion kurtosis imaging has been applied to evaluate white matter and basal ganglia microstructure in mixed Parkinson's disease (PD) groups with inconclusive results. ObjectivesTo evaluate specific patterns of kurtosis changes in PD and to assess the utility of diffusion imaging in differentiating between healthy subjects and cognitively normal PD, and between PD with and without mild cognitive impairment. MethodsDiffusion scans were obtained in 92 participants using 3T MRI. Differences in white matter were tested by tract-based spatial statistics. Gray matter was evaluated in basal ganglia, thalamus, hippocampus, and motor and premotor cortices. Brain atrophy was also assessed. Multivariate logistic regression was used to identify a combination of diffusion parameters with the highest discrimination power between groups. ResultsDiffusion kurtosis metrics showed a significant increase in substantia nigra (p = 0.037, Hedges' g = 0.89), premotor (p = 0.009, Hedges' g = 0.85) and motor (p = 0.033, Hedges' g = 0.87) cortices in PD with normal cognition compared to healthy participants. Combined diffusion markers in gray matter reached 81% accuracy in differentiating between both groups. Significant white matter microstructural changes, and kurtosis decreases in the cortex were present in cognitively impaired versus cognitively normal PD. Diffusion parameters from white and gray matter differentiated between both PD phenotypes with 78% accuracy. ConclusionsIncreased kurtosis in gray matter structures in cognitively normal PD reflects increased hindrance to water diffusion caused probably by alpha-synuclein-related microstructural changes. In cognitively impaired PD, the changes are mostly driven by decreased white matter integrity. Our results support the utility of diffusion kurtosis imaging for PD diagnostics.

Cell type-specific lipid storage changes in Parkinson’s disease patient brains are recapitulated by experimental glycolipid disturbance

Neurons are dependent on proper trafficking of lipids to neighboring glia for lipid exchange and disposal of potentially lipotoxic metabolites, producing distinct lipid distribution profiles among various cell types of the central nervous system. Little is known of the cellular distribution of neutral lipids in the substantia nigra (SN) of Parkinson's disease (PD) patients and its relationship to inflammatory signaling. This study aimed to determine human PD SN neutral lipid content and distribution in dopaminergic neurons, astrocytes, and microglia relative to age-matched healthy subject controls. The results show that while total neutral lipid content was unchanged relative to age-matched controls, the levels of whole SN triglycerides were correlated with inflammation-attenuating glycoprotein non-metastatic melanoma protein B (GPNMB) signaling in human PD SN. Histological localization of neutral lipids using a fluorescent probe (BODIPY) revealed that dopaminergic neurons and midbrain microglia significantly accumulated intracellular lipids in PD SN, while adjacent astrocytes had a reduced lipid load overall. This pattern was recapitulated by experimental in vivo inhibition of glucocerebrosidase activity in mice. Agents or therapies that restore lipid homeostasis among neurons, astrocytes, and microglia could potentially correct PD pathogenesis and disease progression.

In vivo quantification of the locus coeruleus and substantia nigra in parkinson's disease

Objectives: Locus coeruleus (LC) pathology in Parkinson's disease (PD) precedes and may be of even greater magnitude than that in the substantia nigra (SN). Novel magnetic resonance imaging (MRI) techniques now provide an opportunity to visualise and quantify LC degeneration in vivo. In this study we used in vivo T1-weighted Fast Low Angle Shot (FLASH) imaging to assess changes in LC volume and MRI contrast with respect to the SN in idiopathic PD and assessed the relationship to motor and non-motor symptoms.

A Parkinson's disease CircRNAs Resource reveals a link between circSLC8A1 and oxidative stress.

Circular RNAs (circRNAs) are brain‐abundant RNAs of mostly unknown functions. To seek their roles in Parkinson's disease (PD), we generated an RNA sequencing resource of several brain region tissues from dozens of PD and control donors. In the healthy substantia nigra (SN), circRNAs accumulate in an age‐dependent manner, but in the PD SN this correlation is lost and the total number of circRNAs reduced. In contrast, the levels of circRNAs are increased in the other studied brain regions of PD patients. We also found circSLC8A1 to increase in the SN of PD individuals. CircSLC8A1 carries 7 binding sites for miR‐128 and is strongly bound to the microRNA effector protein Ago2. Indeed, RNA targets of miR‐128 are also increased in PD individuals, suggesting that circSLC8A1 regulates miR‐128 function and/or activity. CircSLC8A1 levels also increased in cultured cells exposed to the oxidative stress‐inducing agent paraquat but were decreased in cells treated with the neuroprotective antioxidant regulator drug Simvastatin. Together, our work links circSLC8A1 to oxidative stress‐related Parkinsonism and suggests further exploration of its molecular function in PD.

Calpain mediated expansion of CD4+ cytotoxic T cells in rodent models of Parkinson's disease

Parkinson's disease (PD), a debilitating progressive degenerative movement disorder associated with loss of dopaminergic (DA) neurons in the substantia nigra (SN), afflicts approximately one million people in the U.S., including a significant number of Veterans. Disease characteristics include tremor, rigidity, postural instability, bradykinesia, and at a cellular level, glial cell activation and Lewy body inclusions in DA neurons. The most potent medical/surgical treatments do not ultimately prevent disease progression. Therefore, new therapies must be developed to halt progression of the disease. While the mechanisms of the degenerative process in PD remain elusive, chronic inflammation, a common factor in many neurodegenerative diseases, has been implicated with associated accumulation of toxic aggregated α-synuclein in neurons. Calpain, a calcium-activated cysteine neutral protease, plays a pivotal role in SN and spinal cord degeneration in PD via its role in α-synuclein aggregation, activation/migration of microglia and T cells, and upregulation of inflammatory processes. Here we report an increased expression of a subset of CD4+ T cells in rodent models of PD, including MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mice and DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride]/6-hydroxydopamine rats, which produced higher levels of perforin and granzyme B - typically found in cytotoxic T cells. Importantly, the CD4+ cytotoxic subtype was attenuated following calpain inhibition in MPTP mice, suggesting that calpain and this distinct CD4+ T cell subset may have critical roles in the inflammatory process, disease progression, and neurodegeneration in PD.

A lncRNA survey finds increases in neuroprotective LINC-PINT in Parkinson's disease substantia nigra.

Recent reports highlight regulatory functions of long noncoding RNAs (lncRNAs) in neurodegeneration and aging, but biomedical implications remain limited. Here, we report an rRNA‐depletion‐based long RNA‐Sequencing Resource of 65 substantia nigra, amygdala, and medial temporal gyrus samples from Parkinson's disease (PD) and matched control brains. Using a lncRNA‐focused analysis approach to identify functionally important transcripts, we discovered and prioritized many lncRNAs dysregulated in PD. Those included pronounced elevation of the P53‐induced noncoding transcript LINC‐PINT in the substantia nigra of PD patients, as well as in additional models of oxidative stress and PD. Intriguingly, we found that LINC‐PINT is a primarily neuronal transcript which showed conspicuous increases in maturing primary culture neurons. LINC‐PINT also accumulated in several brain regions of Alzheimer's and Huntington's disease patients and decreased with healthy brain aging, suggesting a general role in aging and neurodegeneration for this lncRNA. RNAi‐mediated depletion of LINC‐PINT exacerbated the death of cultured N2A and SH‐SY5Y cells exposed to oxidative stress, highlighting a previously undiscovered neuroprotective role for this tumor‐inducible lncRNA in the brains of patients with neurodegenerative disorders.

Phase value assessment reveals iron accumulation in parkinson disease

PD is characterized by iron accumulation in the substantia nigra (SN) different from healthy controls. We aim to quantify iron accumulation via susceptibility weighted imaging (SWI) in Parkinson disease (PD). Twenty patients with PD and 21 healthy controls were included in this study. The SWI phase value was evaluated from SN in two areas (middle midbrain and lateral side of middle midbrain) at the axial plane for both sides (right and left). The PD group was divided into two subgroups after clinical examination: the affected side (AS), which was the contralateral of the clinically prominent side and the non-affected side (NAS). The subgroups were analyzed individually. The results of both sides compared between the PD and control groups, as well as between the PD subgroups. The phase values were statistically different in the PD-AS and control group in both areas (< 0.001). Furthermore, at the middle midbrain, the PD-NAS showed a statistical difference compared with the control group (p=0.002). Within the PD groups, only the lateral side of the middle midbrain area (LMMA) demonstrated a statistical difference between the AS and NAS subgroups (p = 0.005). Phase value assessment is useful to demonstrate the effect of iron accumulation on substantia nigra in PD.

Phase value assessment reveals iron accumulation in parkinson disease

PD is characterized by iron accumulation in the substantia nigra (SN) different from healthy controls. We aim to quantify iron accumulation via susceptibility weighted imaging (SWI) in Parkinson disease (PD). Twenty patients with PD and 21 healthy controls were included in this study. The SWI phase value was evaluated from SN in two areas (middle midbrain and lateral side of middle midbrain) at the axial plane for both sides (right and left). The PD group was divided into two subgroups after clinical examination: the affected side (AS), which was the contralateral of the clinically prominent side and the non-affected side (NAS). The subgroups were analyzed individually. The results of both sides compared between the PD and control groups, as well as between the PD subgroups. The phase values were statistically different in the PD-AS and control group in both areas (< 0.001). Furthermore, at the middle midbrain, the PD-NAS showed a statistical difference compared with the control group (p=0.002). Within the PD groups, only the lateral side of the middle midbrain area (LMMA) demonstrated a statistical difference between the AS and NAS subgroups (p = 0.005). Phase value assessment is useful to demonstrate the effect of iron accumulation on substantia nigra in PD.