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| Open AccessPantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism
PKAN and PD are two distinct diseases with overlapping pathophysiology. Here, authors show that their pathogenic genes PANK2 and PINK1 interact. PANK2 regulates mitophagy via CoA metabolism, while PINK1 supervises PANK2 translation on mitochondria.
- Yunpeng Huang
- , Zhihui Wan
- & Bing Zhou
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Article
| Open AccessIntegrating deep learning and unbiased automated high-content screening to identify complex disease signatures in human fibroblasts
By coupling robotic cell culture systems with artificial intelligence–powered image analysis, Schiff et al. identify previously unseen characteristics of Parkinson’s disease in patient skin cells that distinguish them from healthy controls.
- Lauren Schiff
- , Bianca Migliori
- & Bjarki Johannesson
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Article
| Open AccessClueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria
Drp1 is the master regulator of mitochondrial fission, which has important impact on cellular functions. Here, Yang et al identified evolutionarily conserved proteins Clueless and its homolog CLUH as key regulators of Drp1 that function via translation of Drp1 receptors MiD49 and Mff.
- Huan Yang
- , Caroline Sibilla
- & Ming Guo
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| Open AccessMaintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor
Mitochondrial dysfunction in dopaminergic neurons is a pathological hallmark of Parkinson’s disease. Here, the authors find a conserved mechanism by which a single transcription factor controls mitochondrial health in dopaminergic neurons during the aging process.
- Federico Miozzo
- , Eva P. Valencia-Alarcón
- & Emi Nagoshi
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Article
| Open AccessMapping brain structural differences and neuroreceptor correlates in Parkinson’s disease visual hallucinations
Visual hallucinations are a prevalent symptom of Parkinson’s disease. Here the authors use a structural mega-analysis to show cortical regions and networks involved in visual hallucinations and associations with receptor density maps.
- Miriam Vignando
- , Dominic ffytche
- & Mitul A. Mehta
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Article
| Open AccessTargeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism
Here, the authors use cell-type specific stimulation of brainstem neurons within the caudal pedunculopontine nucleus to show that activation of excitatory neurons can normalize severe locomotor deficit in mouse models of parkinsonism. The study defines a potential target for neuromodulatory restoration of locomotor function in Parkinson’s disease.
- Débora Masini
- & Ole Kiehn
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Article
| Open AccessModulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations
Dopamine tone modulation generates changes in beta oscillation physiology. Here the authors show beta frequency, and not power, coherence, phase-locking, or PAC is monotonically linked to dopamine tone and is likely the key property of pathological oscillations in cortical and basal ganglia networks.
- L. Iskhakova
- , P. Rappel
- & H. Bergman
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Article
| Open AccessMicroglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
Whether microglial activation constitutes a primary pathological event in synucleinopathies is not known. Here, the authors generated a mouse model over-expressing α-synuclein in microglial cells and found these mice developed progressive dopaminergic neuron degeneration and microglia developed a reactive, pro-inflammatory state with phagocytic exhaustion.
- Simone Bido
- , Sharon Muggeo
- & Vania Broccoli
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Article
| Open AccessModeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption
Cellular models of organs have been used to investigate mechanisms of disease. Here the authors generate a human alpha synuclein-induced brain-chip model that recapitulates blood-brain barrier dysfunction, as a potential testing platform for novel therapeutics in Parkinson’s disease.
- Iosif Pediaditakis
- , Konstantia R. Kodella
- & Katia Karalis
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Article
| Open AccessMagnetothermal nanoparticle technology alleviates parkinsonian-like symptoms in mice
Deep-brain stimulation ameliorates parkinsonian symptoms, but it usually requires permanent implantation of hardware and connectors. Here, the authors show magnetothermal neuromodulation through the activation of TRPV1 can improve locomotor deficits in mouse models of Parkinson’s disease.
- Sarah-Anna Hescham
- , Po-Han Chiang
- & Yasin Temel
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Article
| Open AccessSelective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo
The mechanisms underlying the spreading of α-synuclein in various α-synucleinopathies are unclear. Here, the authors show that targeting the TLR2/MyD88/NF-κB pathway can reduce α-synuclein spreading, reduce neuroinflammation, and protect dopaminergic neurons in vitro and in mouse models
- Debashis Dutta
- , Malabendu Jana
- & Kalipada Pahan
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Article
| Open AccessNeural signatures of hyperdirect pathway activity in Parkinson’s disease
In Parkinson’s disease (PD), beta frequency oscillations are synchronised across the cortico-basal-ganglia circuit. The authors show in human participants that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway, indicating a pathophysiological role for this pathway in PD.
- Ashwini Oswal
- , Chunyan Cao
- & Vladimir Litvak
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Article
| Open AccessEpigenetic inactivation of the autophagy–lysosomal system in appendix in Parkinson’s disease
Dysfunction of the gastrointestinal system, and to the autophagy lysososmal pathway (ALP) have been reported in Parkinson’s disease. Here the authors report epigenetic disruption of ALP related genes in the appendix of individuals with Parkinson’s disease.
- Juozas Gordevicius
- , Peipei Li
- & Viviane Labrie
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Article
| Open AccessPhenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons
α-Synuclein aggregation contributes to Parkinson’s disease and related disorders. Here the authors investigate patterns of α-synuclein aggregation in human dopaminergic neurons in response to fibrils derived from individuals with Parkinson’s disease or multiple system atrophy.
- Benedict Tanudjojo
- , Samiha S. Shaikh
- & George K. Tofaris
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| Open AccessCytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson’s disease
Mitochondrial and lysosomal dysfunction are central to Parkinson’s disease (PD) pathogenesis. Here, the authors show mitochondrial dsDNA in the cytosol in cellular and Zebrafish models of PD induces cytotoxicity and neurodegeneration; knock-down of IFI16, a cytosolic dsDNA sensor, rescues cytotoxicity, as does overexpression of lysosomal DNAse II.
- Hideaki Matsui
- , Junko Ito
- & Akiyoshi Kakita
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| Open AccessPredicting optimal deep brain stimulation parameters for Parkinson’s disease using functional MRI and machine learning
Deep brain stimulation programming for Parkinson’s disease entails the assessment of a large number of possible simulation settings, requiring numerous clinic visits after surgery. Here, the authors show that patterns of functional MRI can predict the optimal stimulation settings.
- Alexandre Boutet
- , Radhika Madhavan
- & Andres M. Lozano
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Article
| Open AccessIn situ architecture of neuronal α-Synuclein inclusions
The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. Here, authors use cryo-electron tomography to image neuronal α-Syn inclusions in situ and find that inclusions consist of α-Syn fibrils intermixed with cellular organelles without interacting directly.
- Victoria A. Trinkaus
- , Irene Riera-Tur
- & Rubén Fernández-Busnadiego
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| Open AccessDysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease
Mitochondria-lysosome contact sites mediate cross-talk between the two organelles. Here, the authors show mitochondria-lysosome contacts are prolonged and defective in heterozygous mutant GBA1 neurons, which is caused by defective modulation of TBC1D15 due to decreased GBA1 activity.
- Soojin Kim
- , Yvette C. Wong
- & Dimitri Krainc
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Article
| Open AccessThe release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells
The self-assembly of α-synuclein (αS) is a pathological feature of Parkinson’s disease. The αS species responsible for neuronal damage are not well characterized. Here, the authors show that αS fibrils release soluble prefibrillar oligomeric species responsible for neurotoxicity in vitro.
- Roberta Cascella
- , Serene W. Chen
- & Cristina Cecchi
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Article
| Open AccessMetabolomics of sebum reveals lipid dysregulation in Parkinson’s disease
Studies of metabolites in neurodegeneration have not yet used sebum as a source fluid. Here the authors demonstrate the potential of metabolomics of sebum samples from individuals with Parkinson’s disease and controls.
- Eleanor Sinclair
- , Drupad K. Trivedi
- & Perdita Barran
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| Open AccessThe docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition
α-Synuclein is a presynaptic protein whose aberrant aggregation is associated with Parkinson’s disease. Here, the authors show how αSynuclein-induced docking of synaptic vesicles is modulated by the lipid composition changes typically observed in neurodegeneration using an in vitro system.
- Wing K. Man
- , Bogachan Tahirbegi
- & Giuliana Fusco
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Article
| Open AccessBlood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia
Blood brain barrier (BBB) opening is being investigated as a therapeutic approach for neurodegenerative diseases. Here, the authors report the results of a phase I trial to evaluate the feasibility and safety of BBB opening of the right parieto-occipito-temporal cortex in Parkinson´s disease with dementia.
- Carmen Gasca-Salas
- , Beatriz Fernández-Rodríguez
- & José A. Obeso
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Article
| Open AccessGABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model
GABA transporters expressed in the striatum may affect behaviour. Here the authors investigate the contribution of GABA transporters on astrocytes to the regulation of dopamine release in the striatum, and show decreased expression of GAT-1 and GAT-3 in a mouse model of Parkinsonism.
- Bradley M. Roberts
- , Natalie M. Doig
- & Stephanie J. Cragg
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Article
| Open AccessCLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease
CLR01 is a molecular tweezer that inhibits protein aggregation. Here the authors show that CLR01 protects dopaminergic neurons in vitro and in vivo in human neurons and in mouse models showing potential as a disease-modifying therapy for Parkinson’s disease.
- Nora Bengoa-Vergniory
- , Emilie Faggiani
- & Richard Wade-Martins
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Article
| Open AccessA single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders
The substantia nigra is important in neurological disease, particularly movement disorders. Here the authors provide a single cell transcriptomic atlas for the human substantia nigra.
- Devika Agarwal
- , Cynthia Sandor
- & Caleb Webber
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Article
| Open AccessSynucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling
The nanoscale organisation of the brain extracellular space can be studied in vivo. Here, the authors investigate how it changes in response to α-synuclein pathology, and identify interactions between microglia and the extracellular matrix.
- Federico N. Soria
- , Chiara Paviolo
- & Erwan Bezard
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Article
| Open AccessPre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease
Induced pluripotent stem cell (iPSC) derived dopaminergic neurons are a promising source for cell-based Parkinson’s disease (PD) therapy. Here the authors report a comprehensive pre-clinical evaluation of the safety and efficacy of dopaminergic progenitors derived from a clinical-grade human iPSC line.
- Daisuke Doi
- , Hiroaki Magotani
- & Jun Takahashi
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Article
| Open AccessExtent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity
In Parkinson’s disease (PD) the monomeric protein alpha-synuclein (aSyn) misfolds and aggregates into insoluble fibrils. Here the authors use NMR measurements and hydrogen–deuterium exchange mass spectrometry and find that the more solvent exposed the N-terminus of aSyn is, the more aggregation prone its conformation becomes, and further show how PD mutations and post translational modifications influence the extent of the N-terminus solvent exposure.
- Amberley D. Stephens
- , Maria Zacharopoulou
- & Gabriele S. Kaminski Schierle
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Article
| Open AccessDeep brain stimulation-guided optogenetic rescue of parkinsonian symptoms
Deep brain stimulation (DBS) is a symptomatic treatment of Parkinson’s disease (PD) that benefits only a minority of patients. Here, the authors show that activation of cortical somatostatin interneurons alleviates motor symptoms in a mouse model of PD and may constitute a less invasive alternative than DBS.
- Sébastien Valverde
- , Marie Vandecasteele
- & Laurent Venance
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Article
| Open Accessα-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease
α-Synuclein-specific T cell reactivity is preferentially associated with Parkinson’s disease (PD) patients, but the temporal relation with diagnosis was previously unknown. This study reveals that α-syn-reactive T cells are highest before and shortly after diagnosis of motor PD, and then decrease.
- Cecilia S. Lindestam Arlehamn
- , Rekha Dhanwani
- & Alessandro Sette
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| Open AccessAnalysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease
Parkinson’s disease (PD) is a common neurodegenerative disorder with a complex etiology involving genetics and the environment. Here, Vallerga et al. identify two CpG probes associated with PD in a blood cell type-corrected epigenome-wide meta-analysis, implicating the SLC7A11 gene as a plausible biological target.
- Costanza L. Vallerga
- , Futao Zhang
- & Jacob Gratten
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Article
| Open AccessPyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection
Dopamine agonists increase brain glutathione levels. Here the authors identify noncanonical signalling by Nrf2 as a potential mechanism for the neuroprotective effects of dopamine D2 receptor activation.
- Yao Wei
- , Ming Lu
- & Gang Hu
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Article
| Open AccessNon-invasive recording from the human olfactory bulb
Measures of neural processing can be obtained non-invasively from all areas of the human brain but one, the olfactory bulb. Here, the authors show that signals obtained from EEG electrodes at the nasal bridge represent responses from the human olfactory bulb, the so-called Electrobulbogram.
- Behzad Iravani
- , Artin Arshamian
- & Johan N. Lundström
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Article
| Open AccessROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway
Damaged mitochondria are known to cause neuronal death, suggesting clearance as a potential therapy. Here, Moskal et al. show that ROCK inhibitors promote Parkin recruitment and mitophagy and have neuroprotective effects in fruit flies challenged with a toxin that induces mitochondrial damage.
- Natalia Moskal
- , Victoria Riccio
- & G. Angus McQuibban
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| Open AccessLRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients
Mutations in LRRK2 and GBA1, which encodes glucocerebrosidase (GCase), are associated with Parkinson’s disease. Here the authors show that LRRK2 is a negative regulator of lysosomal GCase activity, using dopaminergic neurons derived from iPSCs from PD patients with LRRK2 mutations.
- Daniel Ysselstein
- , Maria Nguyen
- & Dimitri Krainc
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Article
| Open AccessStructural heterogeneity of α-synuclein fibrils amplified from patient brain extracts
Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are characterized by the pathological accumulation of α-synuclein. Here the authors employ fluorescent probes, electron microscopy and NMR spectroscopy to study the properties of α-synuclein aggregates that were amplified from patient brain extracts and observe a greater structural diversity among PD patients compared to MSA patients.
- Timo Strohäker
- , Byung Chul Jung
- & Markus Zweckstetter
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Article
| Open AccessThe landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease
Parkinson’s disease (PD) is characterized by neurodegeneration associated with loss of dopaminergic (DA) neurons and deposition of Lewy bodies. Here, Wang et al. use co-expression network analysis to pinpoint disease pathways and propose reduced expression of STMN2 as a cause of presynaptic function loss in PD.
- Qian Wang
- , Yuanxi Zhang
- & Bin Zhang
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Article
| Open AccessBlunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease
Resolvins are endogenous lipids with pro-resolving activity. Here the authors find that rats overexpressing human α-synuclein show defects in dopamine signalling before dopamine cell loss, and that this is associated with low Resolvin D1 levels and neuroinflammation.
- Paraskevi Krashia
- , Alberto Cordella
- & Nicola Biagio Mercuri
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Article
| Open AccessBrain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis
It is unclear if neuromelanin plays a role in Parkinson’s disease pathogenesis since common laboratory animals lack this pigment. Authors show here that overexpression of human tyrosinase in the substantia nigra of rats resulted in an age-dependent production of human-like neuromelanin within nigral dopaminergic neurons and is associated with a Parkinson’s disease phenotype when allowed to accumulate above a specific threshold.
- Iria Carballo-Carbajal
- , Ariadna Laguna
- & Miquel Vila
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Article
| Open AccessPrioritizing Parkinson’s disease genes using population-scale transcriptomic data
GWAS have identified over 41 susceptibility loci for Parkinson’s disease (PD). Here, the authors integrate PD GWAS summary statistics with transcriptome data from monocytes and DLFPC tissue in a TWAS approach and find 66 significant associations with PD risk highlighting lysosomal and innate immune functions.
- Yang I. Li
- , Garrett Wong
- & Towfique Raj
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Article
| Open AccessSingle-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development
Midbrain dopamine (mDA) neurons are significantly associated with Parkinson’s disease and yet there is no systematic molecular classification of these heterogenous group of cells. Here authors use single cell RNA sequencing of isolated mouse neurons expressing the transcription factor Pitx3 (broad mDA neuronal marker) to identify and characterize seven neuron subgroups divided in two major branches of developing Pitx3-expressing neurons.
- Katarína Tiklová
- , Åsa K. Björklund
- & Thomas Perlmann
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Article
| Open AccessDopamine–endocannabinoid interactions mediate spike-timing-dependent potentiation in the striatum
Dopamine tightly regulates plasticity at corticostriatal synapses. Here, the authors report that endocannabinoid dependent LTP induced with few spikes in the striatum is impaired in a rodent model of Parkinson’s disease, requires dopamine through presynaptic D2 receptors located on corticostriatal inputs.
- Hao Xu
- , Sylvie Perez
- & Laurent Venance
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Article
| Open AccessLRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation
Mutations in LRRK2 kinase are associated with Parkinson’s disease. Here the authors show that LRRK2 modulates propagation of α-synuclein, using rodent and C. elegans models, and show that this is dependent on phosphorylation of one of its substrates, RAB35.
- Eun-Jin Bae
- , Dong-Kyu Kim
- & Seung-Jae Lee
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Article
| Open AccessTLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons
Inflammation is a component of Parkinson’s disease. Here the authors show that activation of Toll-like receptor 9 controlled by microglial glucocorticoid receptor signaling, contributes to dopamine neuron loss in a model of Parkinson’s disease.
- Layal Maatouk
- , Anne-Claire Compagnion
- & Sheela Vyas
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Article
| Open AccessGABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease
Cholinergic interneurons of the striatum are involved reward-related behaviors and have been implicated in Parkinson’s disease. Here the authors report that half of cholinergic neurons co-release acetylcholine and GABA, and study the role of these neurons in a model of Parkinson’s Disease.
- N. Lozovaya
- , S. Eftekhari
- & C. Hammond
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Article
| Open AccessA comprehensive map coupling histone modifications with gene regulation in adult dopaminergic and serotonergic neurons
The limited size of some neuronal types and their entangled environment renders it difficult to study their transcription regulation. Here the authors present a comparative analysis of histone modifications and transcription in dopaminergic and serotonergic neurons and embryonic neural progenitors.
- Erik Södersten
- , Konstantinos Toskas
- & Johan Holmberg
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Article
| Open AccessCardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein
Cardiolipin is a phospholipid component of the inner mitochondrial membrane. Here the authors demonstrate that cardiolipin interacts with mutant α-synuclein, and that impaired cardiolipin function can lead to spread of α-synuclein between neurons.
- Tammy Ryan
- , Vladimir V. Bamm
- & Scott D. Ryan
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Article
| Open AccessImpaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor
Dopamine receptor agonists are used for the treatment of various psychiatric diseases. Here, the authors screen approximately three million compounds and identify a novel class of D1R agonists that do not have a catechol scaffold and possess promising pharmacokinetic properties.
- David L. Gray
- , John A. Allen
- & Michael D. Ehlers
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Article
| Open AccessVentromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder
Loss of muscle tone is a distinguishing feature of paradoxical or REM sleep (PS) and is disrupted in REM sleep behavior disorder. Here the authors report that GABA/glycine inhibitory neurons in the ventromedial medulla are essential for producing PS muscle atonia without affecting PS quantity.
- Sara Valencia Garcia
- , Frédéric Brischoux
- & Patrice Fort