Browsing by Subject "Parkinson's disease"

Now showing 1 - 10 of 49
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    A proteogenomic view of Parkinson's disease causality and heterogeneity
    (Springer Nature, 2023-02-11) Kaiser, Sergio; Zhang, Luqing; Mollenhauer, Brit; Jacob, Jaison; Longerich, Simonne; Del-Aguila, Jorge; Marcus, Jacob; Raghavan, Neha; Stone, David; Fagboyegun, Olumide; Galasko, Douglas; Dakna, Mohammed; Bilican, Bilada; Dovlatyan, Mary; Kostikova, Anna; Li, Jingyao; Peterson, Brant; Rotte, Michael; Sanz, Vinicius; Foroud, Tatiana; Hutten, Samantha J.; Frasier, Mark; Iwaki, Hirotaka; Singleton, Andrew; Marek, Ken; Crawford, Karen; Elwood, Fiona; Messa, Mirko; Serrano-Fernandez, Pablo; Medical and Molecular Genetics, School of Medicine
    The pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into “endotypes”. The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.
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    Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease
    (Wiley, 2014-05) Nuytemans, Karen; Inchausti, Vanessa; Beecham, Gary W.; Wang, Liyong; Dickson, Dennis W.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Mash, Deborah C.; Frosch, Matthew P.; Foroud, Tatiana M.; Honig, Lawrence S.; Montine, Thomas J.; Dawson, Ted M.; Martin, Eden R.; Scott, William K.; Vance, Jeffery M.; Medical & Molecular Genetics, School of Medicine
    BACKGROUND: We have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson's disease (PD) in a clinically diagnosed data set. Because 10% to 25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized that this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders. METHODS: We screened 488 autopsy-confirmed PD cases for expansion haplotype tag rs3849942T. In 196 identified haplotype carriers, the C9ORF72 repeat was genotyped using the repeat-primed polymerase chain reaction assay. RESULTS: No larger (intermediate or expanded) repeats were found in these autopsy-confirmed PD samples. This absence of larger repeats is significantly different from the frequency in clinically diagnosed datasets (P = 0.002). CONCLUSIONS: Our results suggest that expanded or intermediate C9ORF72 repeats in clinically diagnosed PD or parkinsonism might be an indication of heterogeneity in clinically diagnosed PD cases. Further studies are needed to elucidate the potential contribution of the C9ORF72 repeat to autopsy-confirmed PD.
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    Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration
    (Wiley, 2020-08-04) Sun, Ling; Zhang, Jie; Chen, Wenfeng; Chen, Yun; Zhang, Xiaohui; Yang, Mingjuan; Xiao, Min; Ma, Fujun; Yao, Yizhou; Ye, Meina; Zhang, Zhenkun; Chen, Kai; Chen, Fei; Ren, Yujun; Ni, Shiwei; Zhang, Xi; Yan, Zhangming; Sun, Zhi-Rong; Zhou, Hai-Meng; Yang, Hongqin; Xie, Shusen; Haque, M. Emdadul; Huang, Kun; Yang, Yufeng; Medical and Molecular Genetics, School of Medicine
    How complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in Parkinson's disease (PD) is largely unclear. Here, we applied frequent gene co‐expression analysis on human patient substantia nigra‐specific microarray datasets to identify potential novel disease‐related genes. In vivo Drosophila studies validated two of 32 candidate genes, a chromatin‐remodeling factor SMARCA4 and a biliverdin reductase BLVRA. Inhibition of SMARCA4 was able to prevent aging‐dependent dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. Furthermore, down‐regulation of SMARCA4 specifically in the dopaminergic neurons prevented shortening of life span caused by α‐synuclein and LRRK2. Mechanistically, aberrant SMARCA4 and BLVRA converged on elevated ERK‐ETS activity, attenuation of which by either genetic or pharmacological manipulation effectively suppressed dopaminergic degeneration in Drosophila in vivo. Down‐regulation of SMARCA4 or drug inhibition of MEK/ERK also mitigated mitochondrial defects in PINK1 (a PD‐associated gene)‐deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in normal aging and a broad range of age‐related disorders including PD.
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    Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)
    (Springer Nature, 2023-09-13) Lange, Lara M.; Avenali, Micol; Ellis, Melina; Illarionova, Anastasia; Keller Sarmiento, Ignacio J.; Tan, Ai-Huey; Madoev, Harutyun; Galandra, Caterina; Junker, Johanna; Roopnarain, Karisha; Solle, Justin; Wegel, Claire; Fang, Zih-Hua; Heutink, Peter; Kumar, Kishore R.; Lim, Shen-Yang; Valente, Enza Maria; Nalls, Mike; Blauwendraat, Cornelis; Singleton, Andrew; Mencacci, Niccolo; Lohmann, Katja; Klein, Christine; Global Parkinson’s Genetic Program (GP2); Medical and Molecular Genetics, School of Medicine
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    Author Correction: Genetic factors affecting dopaminergic deterioration during the premotor stage of Parkinson disease
    (Springer Nature, 2022-03-09) Lee, Myung Jun; Pak, Kyoungjune; Kim, Han-Kyeol; Nudelman, Kelly N.; Kim, Jong Hun; Kim, Yun Hak; Kang, Junho; Baek, Min Seok; Lyoo, Chul Hyoung; Medical and Molecular Genetics, School of Medicine
    Erratum for: Genetic factors affecting dopaminergic deterioration during the premotor stage of Parkinson disease. Lee MJ, Pak K, Kim HK, Nudelman KN, Kim JH, Kim YH, Kang J, Baek MS, Lyoo CH. NPJ Parkinsons Dis. 2021 Nov 26;7(1):104. doi: 10.1038/s41531-021-00250-2. PMID: 34836969
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    Author Correction: Report from a multidisciplinary meeting on anxiety as a non-motor manifestation of Parkinson’s disease
    (Nature, 2020-06-02) Pontone, Gregory M.; Dissanayaka, Nadeeka; Apostolova, Liana; Brown, Richard G.; Dobkin, Roseanne; Dujardin, Kathy; Friedman, Joseph H.; Leentjens, Albert F. G.; Lenze, Eric J.; Marsh, Laura; Mari, Lynda; Monchi, Oury; Richard, Irene H.; Schrag, Anette; Strafella, Antonio P.; Vernaleo, Beth; Weintraub, Daniel; Mari, Zoltan; Neurology, School of Medicine
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    Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein
    (National Academy of Sciences, 2016-08-23) Wang, Wei; Nguyen, Linh T. T.; Burlak, Christopher; Chegini, Fariba; Guo, Feng; Chataway, Tim; Ju, Shulin; Fisher, Oriana S.; Miller, David W.; Datta, Debajyoti; Wu, Fang; Wu, Chun-Xiang; Landeru, Anuradha; Wells, James A.; Cookson, Mark R.; Boxer, Matthew B.; Thomas, Craig J.; Gai, Wei Ping; Ringe, Dagmar; Petsko, Gregory A.; Hoang, Quyen Q.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.
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    Combating Parkinson's disease-associated toxicity by modulating proteostasis
    (National Academy of Sciences, 2017-01-31) Park, Yangshin; Hoang, Quyen Q.; Biochemistry and Molecular Biology, School of Medicine
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    A Community-Based Occupational Therapy Program for Parkinson's
    (2023-05-02) Stiens, Maria; Hull, Kristin; Department of Occupational Therapy, School of Health and Human Sciences; Williams, Kim
    Parkinson’s disease is a progressive neurological condition that causes symptoms that interrupt safety, performance, and participation in everyday life activities. The literature supports occupational therapy’s role in maximizing quality of life and preventing occupational decline in people with Parkinson’s disease. Despite the effectiveness of occupational therapy treatment with this population, occupational therapy services are under-utilized among those with Parkinson’s disease. This doctoral capstone experience and project sought to increase access to occupational therapy services to individuals with Parkinson’s within the state of Indiana through free occupation-based groups hosted by a local Parkinson’s organization. Through needs assessments and client-centered surveys, the occupational needs and interests of site stakeholders were determined. Fourteen in-person training sessions were created and delivered to two Parkinson group locations within the greater Indianapolis area. There was a total of approximately thirty participants primarily consisting of community-dwelling individuals with Parkinson’s. Post-survey results indicated a positive trend, demonstrating an overall decrease in participants’ perceived difficulty with surveyed tasks. This study supports the continued need for occupation-based education and training for individuals with Parkinson’s.
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    Cortex – basal ganglia synchronization in Parkinson’s disease
    (Office of the Vice Chancellor for Research, 2014-04-11) Zauber, S. Elizabeth; Ahn, Sungwoo; Worth, Robert M.; Witt, Thomas C.; Rubchinsky, Leonid L.
    Increased synchrony in the beta band in cortico-basal ganglia circuits is well described in patients with PD. Less is known, however, about how these abnormal firing patterns are correlated across these brain regions. In this study we investigated how this intra-operative data recorded from STN correlates with scalp recorded EEG. Intraoperative single unit recordings and LFPs were obtained from STN and scalp EEG recordings were collected from four electrodes positioned over prefrontal and motor areas. We computed the STN spike-LFP (Local Filed Potential) phase synchrony over short temporal windows as it fluctuates in time. We also computed the EEG phase synchrony index time series for all 6 pairs of EEG electrodes. Next we explored cross-correlation between the two synchrony level time-series of the spike-LFP vs. EEG pairs. EEG synchrony was found to be correlated with spike-LFP synchrony. Correlation between surface EEG and STN was strongest for ipsilateral EEG and STN recordings. Spike-LFP synchronization is believed to characterize the input-output characteristics of STN dynamics and to be strongly relevant to the expression of motor symptoms. Our results indicate that non-invasive and relatively simple EEG recordings retain some information about synchronous dynamics in the subcortical regions, which can be access only in an invasive manner during functional neurosurgical procedures.