scholarly journals Single-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson’s disease

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Gabriela Novak ◽  
Dimitrios Kyriakis ◽  
Kamil Grzyb ◽  
Michela Bernini ◽  
Sophie Rodius ◽  
...  

AbstractParkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene, which is strongly associated with PD. Single-cell RNA sequencing (RNAseq) and gene expression analysis of a PINK1-ILE368ASN and a control cell line identified genes differentially expressed during mDA neuron differentiation. Network analysis revealed that these genes form a core network, members of which interact with all known 19 protein-coding Parkinson’s disease-associated genes. This core network encompasses key PD-associated pathways, including ubiquitination, mitochondrial function, protein processing, RNA metabolism, and vesicular transport. Proteomics analysis showed a consistent alteration in proteins of dopamine metabolism, indicating a defect of dopaminergic metabolism in PINK1-ILE368ASN neurons. Our findings suggest the existence of a network onto which pathways associated with PD pathology converge, and offers an inclusive interpretation of the phenotypic heterogeneity of PD.

2020 ◽  
Author(s):  
Gabriela Novak ◽  
Dimitrios Kyriakis ◽  
Kamil Grzyb ◽  
Michela Bernini ◽  
Steven Finkbeiner ◽  
...  

Abstract Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The heterogenous pathology and complex underlying mechanisms are only partly understood and there is no treatment able to reverse PD progression. Here, we targeted the disease mechanisms by focusing on the ILE368ASN mutation within the PINK1 (PARK6) gene and systematically characterized midbrain dopaminergic neurons obtained from human induced pluripotent stem cells (iPSCs). Single-cell RNA sequencing (RNAseq) and pairwise analysis of gene expression identified genes consistently differentially expressed during the mDA neuron differentiation process. Subsequent network analysis revealed that these genes form a core network, which interacts with all known 19 protein-coding Parkinson’s disease-associated genes and includes ubiquitination, mitochondrial, protein processing, RNA metabolism, and secretory pathways as important subnetworks. Our findings indicate a unified network underlying PD pathology and offers new interpretation of the phenotypic heterogeneity of PD.


2020 ◽  
Author(s):  
Brett Fulleylove-Krause ◽  
Samantha Sison ◽  
Allison Ebert

Abstract Objectives: Parkinson’s disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. Although the underlying mechanisms of dopaminergic neuron loss is not fully understood, evidence suggests mitochondrial malfunction as a key contributor to disease pathogenesis. We previously found that human PD patient stem cell-derived dopaminergic neurons exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels and reduce activity of sirtuins, a group of NAD+-dependent deacetylase enzymes that participate in the regulation of mitochondrial function, energy production, and cell survival. Thus, here we tested whether treatment of PD stem cell-derived dopaminergic neurons with nicotinamide mononucleotide (NMN), an NAD+ precursor, could increase NAD+ levels and improve sirtuin activity. Results: We treated PD iPSC-derived dopaminergic neurons with NMN and found that NAD+ levels did increase. The deacetylase activity of sirtuin (SIRT) 2 was improved with NMN treatment, but NMN had no impact on deacetylase activity of SIRT 1 or 3. These results suggest that NMN can restore NAD+ levels and SIRT 2 activity, but that additional mechanisms are involved SIRT 1 and 3 dysregulation in PD dopaminergic neurons.


2001 ◽  
Vol 1 ◽  
pp. 207-208 ◽  
Author(s):  
Todd B. Sherer ◽  
Ranjita Betarbet ◽  
J. Timothy Greenamyre

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.


PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009182
Author(s):  
Fiona Dick ◽  
Gonzalo S. Nido ◽  
Guido Werner Alves ◽  
Ole-Bjørn Tysnes ◽  
Gry Hilde Nilsen ◽  
...  

Studies of differential gene expression have identified several molecular signatures and pathways associated with Parkinson’s disease (PD). The role of isoform switches and differential transcript usage (DTU) remains, however, unexplored. Here, we report the first genome-wide study of DTU in PD. We performed RNA sequencing following ribosomal RNA depletion in prefrontal cortex samples of 49 individuals from two independent case-control cohorts. DTU was assessed using two transcript-count based approaches, implemented in the DRIMSeq and DEXSeq tools. Multiple PD-associated DTU events were detected in each cohort, of which 23 DTU events in 19 genes replicated across both patient cohorts. For several of these, including THEM5, SLC16A1 and BCHE, DTU was predicted to have substantial functional consequences, such as altered subcellular localization or switching to non-protein coding isoforms. Furthermore, genes with PD-associated DTU were enriched in functional pathways previously linked to PD, including reactive oxygen species generation and protein homeostasis. Importantly, the vast majority of genes exhibiting DTU were not differentially expressed at the gene-level and were therefore not identified by conventional differential gene expression analysis. Our findings provide the first insight into the DTU landscape of PD and identify novel disease-associated genes. Moreover, we show that DTU may have important functional consequences in the PD brain, since it is predicted to alter the functional composition of the proteome. Based on these results, we propose that DTU analysis is an essential complement to differential gene expression studies in order to provide a more accurate and complete picture of disease-associated transcriptomic alterations.


2020 ◽  
Author(s):  
Brett K. Fulleylove-Krause ◽  
Samantha L. Sison ◽  
Allison D. Ebert

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra that leads to severe motor and non-motor deficits. Although the underlying mechanisms of dopaminergic neuron loss is not entirely clear, increasing evidence suggests mitochondrial malfunction as a key contributor to disease pathogenesis. Recently, we found that human PD patient stem cell-derived dopaminergic neurons exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels, an essential cofactor in mitochondrial function and cellular metabolism. In addition, we found that sirtuins, a group of NAD+-dependent deacetylase enzymes that participate in the regulation of mitochondrial function, energy production, and cell survival, displayed decreased activity in PD dopaminergic neurons, thereby suggesting a potential mechanism for dopaminergic loss in PD. Thus, here we tested whether treatment of PD stem cell-derived dopaminergic neurons with an NAD+ precursor could increase NAD+ levels and improve sirtuin activity.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jeann L. Sabino-Carvalho ◽  
James P. Fisher ◽  
Lauro C. Vianna

Parkinson’s disease (PD) is a common neurodegenerative disorder classically characterized by symptoms of motor impairment (e.g., tremor and rigidity), but also presenting with important non-motor impairments. There is evidence for the reduced activity of both the parasympathetic and sympathetic limbs of the autonomic nervous system at rest in PD. Moreover, inappropriate autonomic adjustments accompany exercise, which can lead to inadequate hemodynamic responses, the failure to match the metabolic demands of working skeletal muscle and exercise intolerance. The underlying mechanisms remain unclear, but relevant alterations in several discrete central regions (e.g., dorsal motor nucleus of the vagus nerve, intermediolateral cell column) have been identified. Herein, we critically evaluate the clinically significant and complex associations between the autonomic dysfunction, fatigue and exercise capacity in PD.


Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 579
Author(s):  
Melissa Vos ◽  
Christine Klein

Parkinson’s disease (PD) is a complex neurodegenerative disorder that is currently incurable. As a consequence of an incomplete understanding of the etiology of the disease, therapeutic strategies mainly focus on symptomatic treatment. Even though the majority of PD cases remain idiopathic (~90%), several genes have been identified to be causative for PD, facilitating the generation of animal models that are a good alternative to study disease pathways and to increase our understanding of the underlying mechanisms of PD. Drosophila melanogaster has proven to be an excellent model in these studies. In this review, we will discuss the different PD models in flies and key findings identified in flies in different affected pathways in PD. Several molecular changes have been identified, of which mitochondrial dysfunction and a defective endo-lysosomal pathway emerge to be the most relevant for PD pathogenesis. Studies in flies have significantly contributed to our knowledge of how disease genes affect and interact in these pathways enabling a better understanding of the disease etiology and providing possible therapeutic targets for the treatment of PD, some of which have already resulted in clinical trials.


2020 ◽  
Vol 21 (5) ◽  
pp. 509-518 ◽  
Author(s):  
Omid Reza Tamtaji ◽  
Tooba Hadinezhad ◽  
Maryam Fallah ◽  
Arash Rezaei Shahmirzadi ◽  
Mohsen Taghizadeh ◽  
...  

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNc). PD is a multifactorial disorder, with several different factors being suggested to play a synergistic pathophysiological role, including oxidative stress, autophagy, underlying pro-inflammatory events and neurotransmitters abnormalities. Overall, PD can be viewed as the product of a complex interaction of environmental factors acting on a given genetic background. The importance of this subject has gained more attention to discover novel therapies to prevent as well as treat PD. According to previous research, drugs used to treat PD have indicated significant limitations. Therefore, the role of flavonoids has been extensively studied in PD treatment. Quercetin, a plant flavonol from the flavonoid group, has been considered as a supplemental therapy for PD. Quercetin has pharmacological functions in PD by controlling different molecular pathways. Although few studies intended to evaluate the basis for the use of quercetin in the context of PD have been conducted so far, at present, there is very little evidence available addressing the underlying mechanisms of action. Various principal aspects of these treatment procedures remain unknown. Here, currently existing knowledge supporting the use of quercetin for the clinical management of PD has been reviewed.


2019 ◽  
Vol 14 (2) ◽  
pp. 107-121
Author(s):  
Neeraj Kumar ◽  
Anita Singh ◽  
Dinesh Kumar Sharma ◽  
Kamal Kishore

Background: The humans can be affected by more than 100 types of cancers in which about 22 % cancer death are caused by tobacco, 10% due to alcohol and obesity, 5-10 % by genetic defects and 20 % by infections. Rheumatoid arthritis, an autoimmune disorder, occurs mostly in middle age, affects 2.5 times more to females than males and till 2015, more than 24.5 Million people get affected from this disorder. The deaths due to rheumatoid arthritis were 28000 in 1990 and increased to 38000 in 2013. Parkinson’s disease, a neurodegenerative disorder of central nervous system affects about 6.2 million people in 2015 and responsible for approximately 117400 deaths worldwide. Parkinson’s disease occurs mainly over the age of 60 and males get more affected than females. Methods: Bibliographic database has created by mendeley desktop software for available literature in peer reviewed research articles especially by titles and disease names as keywords with AND Boolean operator (title AND year or author AND year). The intervention and findings of quality papers were extracted by detailed study and a conceptual framework has developed. Results: Total 121 research and review articles are cited in this review to produce high impact in literature for pathophysiology and receptors involved in all three diseases. Changes in enzyme action, prohibition of angiogenesis and inhibition of microtubule are the main areas where anticancer molecules may perform significant effect. The immune system is not a good target for rheumatic treatment due to many complications that occur in body but fibroblast, like synoviocytes, proteases which are responsible for cartilage destruction and osteoclast differentiation may be the beneficial targets for pharmacoactive molecules in the treatment of rheumatoid arthritis. In Parkinson’s disease, supply of dopamine to brain from outside results in brain dopamine synthesis decrement which increase drug dependency. The compounds which stimulate secretion, reuptake inhibitor and increment in dopaminergic neurons may be good targets. Conclusion: Alteration of signal transduction by a drug is the goal of chemogenomics, a new branch formed by combination of chemistry and genomics. The proliferation, angiogenesis and apoptosis of cancer cells are regulated by cellular signaling of transcription factors, protein kinases, transmembrane receptors, extracellular ligands and some external factors like oncogenic mutations, ubiquitin-proteasome pathway with epigenetic changes. Traditional anticancer drugs either alter DNA synthesis or control cell division while new drugs retard tumor growth or induce apoptosis. The deterioration of dopaminergic neurons in substantia nigra results in Parkinson’s disease with mental confusion, cognitive dysfunction and sleep disorder. Rheumatoid arthritis is characterized by inflammation, autoimmunity, joint destruction, deformity and premature mortality and treated mainly by anti-inflammatory and antirheumatic drugs. This review provides a comprehensive summary of objects which may act as potential targets for many health disorders.


2020 ◽  
Author(s):  
Depanjan Sarkar ◽  
Drupad Trivedi ◽  
Eleanor Sinclair ◽  
Sze Hway Lim ◽  
Caitlin Walton-Doyle ◽  
...  

Parkinson’s disease (PD) is the second most common neurodegenerative disorder for which identification of robust biomarkers to complement clinical PD diagnosis would accelerate treatment options and help to stratify disease progression. Here we demonstrate the use of paper spray ionisation coupled with ion mobility mass spectrometry (PSI IM-MS) to determine diagnostic molecular features of PD in sebum. PSI IM-MS was performed directly from skin swabs, collected from 34 people with PD and 30 matched control subjects as a training set and a further 91 samples from 5 different collection sites as a validation set. PSI IM-MS elucidates ~ 4200 features from each individual and we report two classes of lipids (namely phosphatidylcholine and cardiolipin) that differ significantly in the sebum of people with PD. Putative metabolite annotations are obtained using tandem mass spectrometry experiments combined with accurate mass measurements. Sample preparation and PSI IM-MS analysis and diagnosis can be performed ~5 minutes per sample offering a new route to for rapid and inexpensive confirmatory diagnosis of this disease.


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