Featured
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| Open AccessEfficient generation of a self-organizing neuromuscular junction model from human pluripotent stem cells
Here, Urzi et al. pioneered a 2D self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells, with implications for neuromuscular disease modeling and drug screening approaches.
- Alessia Urzi
- , Ines Lahmann
- & Mina Gouti
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Article
| Open AccessD-serine reconstitutes synaptic and intrinsic inhibitory control of pyramidal neurons in a neurodevelopmental mouse model for schizophrenia
Modulation of NMDA receptors via D-serine has been investigated as therapeutic strategy in schizophrenia. Here the authors show that D-serine rescues synaptic and intrinsic inhibitory control of cingulate pyramidal neurons, via modulation of parvalbumin neuron excitability, in a mouse model of neurodevelopmental cognitive dysfunction.
- Xiao-Qin Zhang
- , Le Xu
- & Hao-Wei Shen
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Article
| Open AccessLate gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa
Is there a critical period to deliver gene therapies in photoreceptor degeneration? Using a mouse model of retinitis pigmentosa, the authors show that once 70% of rods are lost, gene replacement fails to restore normal retinal output.
- Miranda L. Scalabrino
- , Mishek Thapa
- & Greg D. Field
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Article
| Open AccessEnhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells
The differentiation of human pluripotent stem cells into dopaminergic neurons is challenging. Here, the authors developed lineage-restricted undifferentiated stem cells, which have an enhanced ability for differentiating into dopaminergic neurons.
- Muyesier Maimaitili
- , Muwan Chen
- & Mark Denham
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Article
| Open AccessPhox2b-expressing neurons contribute to breathing problems in Kcnq2 loss- and gain-of-function encephalopathy models
Kcnq2 disfunction can cause developmental and epileptic encephalopathy (DEE). Here, authors show loss or gain of Kcnq2 function in Phox2b-expressing neurons disrupts breathing, thus identifying these cells as a likely basis for DEE breathing problems.
- J. Soto-Perez
- , C. M. Cleary
- & D. K. Mulkey
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Article
| Open AccessInvestigation of monoclonal antibody CSX-1004 for fentanyl overdose
Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.
- Paul T. Bremer
- , Emily L. Burke
- & Rajeev I. Desai
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Article
| Open AccessEnhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice
Ketamine produces rapid antidepressant effects, but the mechanism involved is not fully understood. Here the authors show that ketamine enhances glutamatergic neurotransmission and produces rapid antidepressant-like effects though recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice.
- Shi-Ge Xue
- , Jin-Gang He
- & Jian-Guo Chen
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Article
| Open AccessOpposing brain signatures of sleep in task-based and resting-state conditions
The associations between sleep, depression and brain activity are not well understood. Here, the authors show patterns of brain activity associated with insomnia and depression resemble those found in people who sleep less, but only under cognitive load. At rest, these activation patterns are hyperconnected and resemble those found in longer sleepers.
- Mohamed Abdelhack
- , Peter Zhukovsky
- & Daniel Felsky
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Article
| Open AccessEndogenous noise of neocortical neurons correlates with atypical sensory response variability in the Fmr1−/y mouse model of autism
Enhanced variability is a hallmark of atypical sensory processing in autism. Here, focusing on variability of neocortical tactile responses in mice, the authors explore the role of endogenous noise sources in neural processing in a model of autism.
- Arjun A. Bhaskaran
- , Théo Gauvrit
- & Andreas Frick
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Article
| Open AccessWake slow waves in focal human epilepsy impact network activity and cognition
Slow waves in sleep are crucial for homeostatic regulation of brain function. Here the authors show similar slow wave activity occurs during wakefulness in people with epilepsy to counter the impact of abnormal, epileptic, brain activity.
- Laurent Sheybani
- , Umesh Vivekananda
- & Matthew C. Walker
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Article
| Open AccessCell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease
Alzheimer’s disease genetic risk is enriched in glial genes. Here, the authors derive cell-type-specific polygenic risk scores and link astrocytic genes with Aβ, and microglial genes with Aβ, tau, microglial activation, and cognitive decline.
- Hyun-Sik Yang
- , Ling Teng
- & Reisa A. Sperling
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Article
| Open AccessINPP5D regulates inflammasome activation in human microglia
INPP5D/SHIP1 is a microglial-expressed gene that has been associated with Alzheimer’s disease through genetic studies. This study reveals that reduction in INPP5D activity induces activation of the NLRP3-inflammasome in human microglia.
- Vicky Chou
- , Richard V. Pearse II
- & Tracy L. Young-Pearse
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Article
| Open AccessThe genetic relationships between brain structure and schizophrenia
Schizophrenia is considered a brain disorder. Here, authors show genetic overlap between brain structure and schizophrenia that was strongest in the hubs of structural covariance networks and concentrated three chromosomal regions.
- Eva-Maria Stauffer
- , Richard A. I. Bethlehem
- & Edward T. Bullmore
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Article
| Open AccessNR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease
Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.
- Haakon Berven
- , Simon Kverneng
- & Charalampos Tzoulis
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Article
| Open AccessResting-state global brain activity affects early β-amyloid accumulation in default mode network
Why β-amyloid plaque initially accumulates in the default mode network of the cortex before Alzheimer’s disease diagnosis is not known. Here, the authors show that this accumulation is associated with a reduction of global brain activity in these regions.
- Feng Han
- , Xufu Liu
- & Xiao Liu
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Article
| Open AccessDiversity of cortical activity changes beyond depression during Spreading Depolarizations
Spreading depolarizations are classically thought to be associated with depression of cortical activity. Here, authors show variable, from depression to booming, changes in cortical activity during different types of spreading depolarizations.
- Azat Nasretdinov
- , Daria Vinokurova
- & Roustem Khazipov
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Article
| Open AccessA reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease
Mitochondrial dysfunction is a contributing factor in Parkinson’s disease. Here the authors carry out a multilayered omics analysis of Parkinson’s disease patient-derived neuronal cells, which reveals a reversible hypometabolism mediated by α-ketoglutarate dehydrogenase deficiency, which is correlated with disease progression in the donating patients.
- Sebastian Schmidt
- , Constantin Stautner
- & Wolfgang Wurst
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Article
| Open AccessEarly-to-mid stage idiopathic Parkinson’s disease shows enhanced cytotoxicity and differentiation in CD8 T-cells in females
Men are at a greater risk to develop Parkinson’s disease (PD). However, Hefeng and team revealed enhanced cytotoxicity and terminal differentiation in CD8 T cells of early-to-mid stage idiopathic PD, especially for females, using systems immunology.
- Christophe M. Capelle
- , Séverine Ciré
- & Feng Q. Hefeng
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Article
| Open AccessA primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson’s disease
Using animal models to mimic Parkinson’s disease can advance our understanding of pathogenesis. Here, the authors combine single-cell genomics with a primate model of parkinsonism to provide insights into neuronal vulnerability and resilience.
- Lei Tang
- , Nana Xu
- & Sheng Liu
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Article
| Open AccessMesenchymal stromal cells alleviate depressive and anxiety-like behaviors via a lung vagal-to-brain axis in male mice
Major depressive disorder is a major public health problem. Here, the authors illustrate that mesenchymal stromal cells exert antidepressant and anxiolytic effects through a pulmonary vagal→ nucleus tractus solitarius → 5-HT dorsal raphe nucleus neural pathway in murine depression models.
- Jing Huang
- , Weijun Huang
- & Andy Peng Xiang
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Article
| Open AccessAltered corollary discharge signaling in the auditory cortex of a mouse model of schizophrenia predisposition
Schizophrenia patients are impaired in attenuating responses to self-generated sensory input. Here, the authors reveal the same sensory deficit and reduced corollary discharge signaling in mice carrying a major genetic risk factor for schizophrenia.
- Brian P. Rummell
- , Solmaz Bikas
- & Torfi Sigurdsson
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Article
| Open AccessTargeted suppression of mTORC2 reduces seizures across models of epilepsy
A loss of neuronal network resilience results in epilepsy. In this study, the authors show that inhibition of mTORC2 suppresses seizures in animal models with multiple aetiologies, thus enhancing neuronal resilience to the pathological hypersynchrony associated with epilepsy.
- James Okoh
- , Jacqunae Mays
- & Mauro Costa-Mattioli
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Article
| Open AccessKnockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model
USP30 has been proposed to regulate mitophagy, a relevant Parkinson’s disease mechanism. Here, the authors show that Usp30 knockout mice and USP30 inhibitors like MTX115325 demonstrate neuroprotective responses in an alpha-synuclein mouse model of Parkinson’s disease.
- Tracy-Shi Zhang Fang
- , Yu Sun
- & David K. Simon
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Article
| Open AccessDaily rhythm in cortical chloride homeostasis underpins functional changes in visual cortex excitability
Ionic levels in neurons provide the potential energy for all neuronal communication. Here the. authors show a very large modulation of [Cl-]i neocortical pyramidal cells, from day to night, with marked effects on cortical excitability and processing.
- Enrico Pracucci
- , Robert T. Graham
- & Gian-Michele Ratto
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Article
| Open AccessIntegrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging
The normal function of amyloid precursor protein (APP) implicated in Alzheimer’s disease is unclear. Here, authors use multi-omics to reveal the fly APP’s role in regulating proteostasis and validate using vertebrate and In-vivo tauopathy models.
- Vanitha Nithianandam
- , Hassan Bukhari
- & Mel B. Feany
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Article
| Open AccessDissecting the human leptomeninges at single-cell resolution
The meninges protect the central nervous system at the brain border, and its dysfunction can lead to neural inflammation and cell damage. Here, the authors uncover the gene signatures of diverse cell types in the aged human leptomeninges and highlight their changes in Alzheimer’s Disease.
- Nicola A. Kearns
- , Artemis Iatrou
- & Yanling Wang
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Article
| Open AccessCross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy
Progressive supranuclear palsy is a devastating neurological disorder without treatment. Here, the authors leveraged omics data and model organisms to nominate, prioritize, and validate high-confidence candidate genes as therapeutic targets.
- Yuhao Min
- , Xue Wang
- & Nilüfer Ertekin-Taner
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Article
| Open AccessA neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer’s disease
The mechanisms that underlie cognitive resilience during aging are poorly understood. Here, the authors describe a neurodegeneration checkpoint response mediated by the transcription factor REST that protects against the onset of Alzheimer’s disease.
- Liviu Aron
- , Chenxi Qiu
- & Bruce A. Yankner
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Article
| Open AccessDeep brain stimulation of thalamic nucleus reuniens promotes neuronal and cognitive resilience in an Alzheimer’s disease mouse model
The mechanisms that confer cognitive resilience to Alzheimer’s disease are not fully understood. Here, the authors uncover the role of the nucleus reuniens in promoting resilience through the suppression of hyperexcitability and the restoration of circuit-level homeostasis to prevent memory decline.
- Shiri Shoob
- , Nadav Buchbinder
- & Inna Slutsky
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Article
| Open AccessMicroglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects
Demyelination is often suggested to cause axonal degeneration. Here, the authors study mice carrying distinct PLP defects and reveal how persistent ensheathment with perturbed myelin poses a risk for CD8 + T cell-driven axon loss and behavioral decline.
- Janos Groh
- , Tassnim Abdelwahab
- & Rudolf Martini
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Article
| Open Accessα-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice
α-Synuclein aggregates in Lewy bodies (LBs) have not been widely used for research due to the limited availability of diseased brains. Here, the authors report a mouse model that recapitulates LB diseases using the LB amplification method.
- Norihito Uemura
- , Nicholas P. Marotta
- & Virginia M.-Y. Lee
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Article
| Open AccessVentral striatal islands of Calleja neurons bidirectionally mediate depression-like behaviors in mice
Ventral striatal Islands of Calleja neurons, known to regulate grooming in mice, are reported to bidirectionally mediate depression-like behaviors. Here, authors link grooming, dopamine signaling and affective behaviors via ventral striatal circuits.
- Yun-Feng Zhang
- , Jialiang Wu
- & Minghong Ma
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Article
| Open AccessMultivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density
Cognitive impairment in Alzheimer’s disease is associated with Tau at the postsynapse. We show that multivalent Tau interactions arrest in vitro condensates and clusters mimicking the postsynaptic density that may result in synaptic dysfunction.
- Zheng Shen
- , Daxiao Sun
- & Markus Zweckstetter
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Article
| Open AccessTranscriptional dissection of symptomatic profiles across the brain of men and women with depression
Recent research sheds light on sex-specific molecular changes in the brains of MDD patients, but their association with specific symptoms is still uncertain. Here, the authors revealed the existence of gene signatures underlying the expression of distinct symptom domains in the brain of men and women with depression.
- Samaneh Mansouri
- , André M. Pessoni
- & Benoit Labonté
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Article
| Open AccessThe endocannabinoid N-arachidonoyl dopamine is critical for hyperalgesia induced by chronic sleep disruption
Generalized body pain and headaches are common experience after sleep disruption. How does sleep disruption lead to generalized pain is unknown. Here, authors reveal that N-arachidonoyl dopamine, an endocannabinoid, is critically implicated in pain perception after sleep disruption.
- Weihua Ding
- , Liuyue Yang
- & Shiqian Shen
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Article
| Open AccessFSH and ApoE4 contribute to Alzheimer’s disease-like pathogenesis via C/EBPβ/δ-secretase in female mice
Follicle stimulating hormone (FSH) has been shown to Alzheimer’s disease like pathology in rodent models. Here the authors show using cellular and animal models that ApoE4 and FSH collectively act to trigger AD-like pathogenesis, by activating C/EBPβ/δ-secretase signalling.
- Jing Xiong
- , Seong Su Kang
- & Keqiang Ye
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Article
| Open AccessNeural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy
PACS1 syndrome is caused by an Arg203Trp mutation in PACS1. Here, the authors show that PACS1R203Wdysregulates HDAC6 to disturb neuronal structure and function in a mouse model, and that silencing PACS1R203W/HDAC6 reverses these deficits.
- Sabrina Villar-Pazos
- , Laurel Thomas
- & Gary Thomas
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Article
| Open AccessKDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors
Zhang et al. report that KDM2B-∆CxxC activated Wnt signaling in the developing hippocampi, where the migration and differentiation of neural progenitors were blocked. KDM2B-∆CxxC mice exhibited defects of hippocampal morphology and related behaviors.
- Bo Zhang
- , Chen Zhao
- & Yan Zhou
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Article
| Open AccessDevelopmental atlas of phase-amplitude coupling between physiologic high-frequency oscillations and slow waves
It remains unclear how cortical high-frequency oscillations (HFOs) and their relation with slow waves change with age. Here, the authors found that while HFO rate widely decreases over time, its coupling with slow waves strengthens in the occipital lobe during childhood.
- Kazuki Sakakura
- , Naoto Kuroda
- & Eishi Asano
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Comment
| Open AccessGlucocerebrosidase mutations disrupt the lysosome and now the mitochondria
β-Glucocerebrosidase (GCase) mutations lead to glucosylceramide build-up in the lysosome, impacting α-synuclein aggregation and autophagy. Recently, Baden and colleagues found GCase in mitochondria, supporting mitochondrial complex I function and energy metabolism. We believe the newly described role of GCase in the mitochondria will inform new Parkinson’s and Gaucher’s disease therapeutics.
- Andrés D. Klein
- & Tiago Fleming Outeiro
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Article
| Open AccessSubventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke
The functions of newborn cells arising from the subventricular zone in response to stroke have been unclear. Here, the authors show that cells migrating from the subventricular zone after stroke promote brain repair and functional recovery in mice.
- Michael R. Williamson
- , Stephanie P. Le
- & Michael R. Drew
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Article
| Open AccessIntegration of 3D-printed cerebral cortical tissue into an ex vivo lesioned brain slice
Brain injuries can result in significant damage to the cerebral cortex, and restoring the cellular architecture of the tissue remains challenging. Here, the authors use a droplet printing technique to fabricate a simplified human cerebral cortical column and demonstrate its functionality and potential for future personalized therapy approaches.
- Yongcheng Jin
- , Ellina Mikhailova
- & Hagan Bayley
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Article
| Open AccessPIWI-interacting RNA expression regulates pathogenesis in a Caenorhabditis elegans model of Lewy body disease
piRNAs are small noncoding RNAs whose biological functions are not fully understood. Here, the authors demonstrate using C. elegans genetic models that dysregulated piRNAs are associated with protein degradation processes in a model of Lewy body disease.
- Xiaobing Huang
- , Changliang Wang
- & Garry Wong
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Article
| Open AccessIctogenesis proceeds through discrete phases in hippocampal CA1 seizures in mice
Predicting seizure onsets may allow for seizure prevention in patients. Here, authors show two distinct phases that always preceded temporal lobe seizures in mice, with activity confined within these two phases failing to progress into a seizure.
- John-Sebastian Mueller
- , Fabio C. Tescarollo
- & Hai Sun
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Article
| Open AccessC9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9
The role of microglia in amyotrophic lateral sclerosis (ALS) is unclear. Here, the authors show that iPSC microglia from C9orf72-ALS patients are toxic to motor neurons and identify microglial MMP9 as a potential therapeutic target.
- Björn F. Vahsen
- , Sumedha Nalluru
- & Kevin Talbot
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Article
| Open AccessAcetylation discriminates disease-specific tau deposition
The authors show that acetylation enhances the aggregation of 3R tau, while blocking the aggregation of 4R tau, providing a molecular basis for disease- and isoform-specific tau deposition.
- Pijush Chakraborty
- , Gwladys Rivière
- & Markus Zweckstetter
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Article
| Open AccessCircadian clock disruption promotes the degeneration of dopaminergic neurons in male Drosophila
Circadian disruptions are frequent comorbidities of neurodegenerative disorders, such as Parkinson’s, marked by dopaminergic neuron loss. Here, the authors reveal circadian clocks dictate the susceptibility of dopamine neurons to oxidative stress.
- Michaëla Majcin Dorcikova
- , Lou C. Duret
- & Emi Nagoshi
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Article
| Open AccessProsaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents
Prosaposin (PSAP) variants are linked to Parkinson’s disease (PD). Here, the authors report PSP changes in PD and lipid dyshomeostasis and PD-like phenotypes in mice lacking PSAP in dopamine neurons; PSAP overexpression counteracts experimental PD.
- Yachao He
- , Ibrahim Kaya
- & Per Svenningsson
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Article
| Open AccessDivergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation
Non-coding repeat expansion in the C9ORF72 gene is the most frequent cause of ALS and frontotemporal dementia. Here, the authors performed single cell analyses of gene expression and epigenetic regulation in these patients’ brains and emphasized the role of astrocytes and neurons in neurodegeneration.
- Junhao Li
- , Manoj K. Jaiswal
- & Stella Dracheva
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