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Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology
The impact of α-synuclein aggregates on neurons has been unclear. Here, the authors identify a Lewy Associated Molecular Dysfunction from Aggregates (LAMDA) signature in inclusion bearing neurons in human brain and a mouse model of α-synucleinopathy.
- Thomas M. Goralski
- , Lindsay Meyerdirk
- & Michael X. Henderson
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| Open Access
The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions
Mitochondria emerged as essential actors of neural circuits development. Here, the authors uncovered that the AMPK-related kinase NUAK1 controls axonal mitochondrial metabolism through the regulation of the mitochondrial microprotein BRAWNIN.
- Marine Lanfranchi
- , Sozerko Yandiev
- & Julien Courchet
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| Open Access
Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons
G protein responses mediated by GPCRs may differ depending on their environment. Here, using highly sensitive Gi/o sensors, the authors reveal the specific pharmacological and Gi/o protein responses of some native GPCRs in neurons, and the influence of G protein composition.
- Chanjuan Xu
- , Yiwei Zhou
- & Jianfeng Liu
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A spatially-resolved transcriptional atlas of the murine dorsal pons at single-cell resolution
The dorsal pons in the brainstem is packed with clusters of neurons, including the parabrachial nucleus, that are involved in many vital functions. Here, authors use single nucleus RNA sequencing and MERFISH to create a spatially defined transcriptional atlas of this region.
- Stefano Nardone
- , Roberto De Luca
- & Bradford B. Lowell
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| Open Access
Specification of neural circuit architecture shaped by context-dependent patterned LAR-RPTP microexons
LAR-RPTPs are presynaptic cell-adhesion proteins that regulate the synaptic properties. Here, LAR-RPTP microexon expression is profiled in region-, cell-type- and circuit-specific contexts and its physiological significance in encoding synaptic architecture is demonstrated.
- Kyung Ah Han
- , Taek-Han Yoon
- & Jaewon Ko
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Regulation of stress granule formation in human oligodendrocytes
Oligodendrocyte (OL) injury and loss is a pathologic hallmark of multiple sclerosis. Here, the authors show the presence of stress granules in OLs in multiple sclerosis lesions, and their in vitro studies in human OLs indicate that stress granules formation is a response to a combination of metabolic stress and pro-inflammatory conditions.
- Florian Pernin
- , Qiao-Ling Cui
- & Jack P. Antel
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| Open Access
Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase
Neurodegenerative diseases often co-accumulate several disease-associated proteins. Here, the authors show that reduction of progranulin, a protein associated with TDP-43, also increases accumulation of tau and a-synuclein via glucocerebrosidase.
- Hideyuki Takahashi
- , Sanaea Bhagwagar
- & Stephen M. Strittmatter
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| Open Access
Ultracompact mirror device for forming 20-nm achromatic soft-X-ray focus toward multimodal and multicolor nanoanalyses
Optics used for X-ray focusing suffer from wavelength dependent effects like chromatic aberration. Here the authors demonstrate fabrication of a ultracompact Kirkpatrick-Baez mirror and use it for achromatic focusing to 20 nm spot for the soft X-ray at 2-keV photon energy.
- Takenori Shimamura
- , Yoko Takeo
- & Hidekazu Mimura
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| Open Access
A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1
In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.
- Ling Hai
- , Dirk C. Hoffmann
- & Tobias Kessler
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| Open Access
Sensory Schwann cells set perceptual thresholds for touch and selectively regulate mechanical nociception
Schwann cells associated with most sensory receptors in the skin actively participate in the transduction of mechanical stimuli. Here the authors show that silencing these sensory Schwann cells is sufficient to reduce touch perception and can inhibit mechanical pain in mice.
- Julia Ojeda-Alonso
- , Laura Calvo-Enrique
- & Gary R. Lewin
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Article
| Open Access
The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity
Blood vessel integrity is critical to maintain brain health. Here, the authors show that both the liver and the muscles secrete HFE2, a protein that promotes blood vessel integrity in healthy animals and in an animal model for multiple sclerosis.
- Xue Fan Wang
- , Robin Vigouroux
- & Philippe P. Monnier
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| Open Access
Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder
Dysfunction in dorsal striatum, a brain region important for reward and habits, is linked to opioid use disorder (OUD). Here, authors delineate diverse cell populations in human dorsal striatum, revealing altered inflammatory and DNA damage signaling in OUD.
- BaDoi N. Phan
- , Madelyn H. Ray
- & Ryan W. Logan
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| Open Access
Sex dependence of opioid-mediated responses to subanesthetic ketamine in rats
In rats, functional ultrasound imaging reveals that blocking opioid receptors modulates the effects of subanesthetic ketamine on neural activity in males but not in females, with parallel changes in ketamine’s effects on brain structure and behavior.
- Tommaso Di Ianni
- , Sedona N. Ewbank
- & Raag D. Airan
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iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity
PACS1 syndrome is a neurodevelopmental disorder resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). Here the authors use cortical organoids to investigate the impact of this variant on neurodevelopment.
- Lauren Rylaarsdam
- , Jennifer Rakotomamonjy
- & Alicia Guemez-Gamboa
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| Open Access
Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice
Traditional systematic anti-seizure treatments alter brain-wide activity and often carry significant side effects. The authors engineered an inhibitory, acetylcholine receptor-based, chemogenetic tool to suppress targeted neurons, enabling control of chronic seizures in mice.
- Quynh-Anh Nguyen
- , Peter M. Klein
- & Ivan Soltesz
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Molecular basis of human trace amine-associated receptor 1 activation
hTA1 is a drug target for several neuropsychiatric disorders. Using cryo-EM and pharmacological assays, the authors illuminate hTA1’s similarity to neurotransmitter receptors and discover that the antipsychotic asenapine potently activates the receptor.
- Gregory Zilberg
- , Alexandra K. Parpounas
- & Daniel Wacker
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Prion protein conversion at two distinct cellular sites precedes fibrillisation
In this work, the authors investigated the cellular mode of prion propagation. The report that proteopathic seeds of abnormal PrP are N-terminally truncated and detected within minutes after infection. These seeds reach the plasma membrane by regulated secretory pathways where phenotypically distinct fibril-like PrP aggregates are formed with a lag of 24 h after infection.
- Juan Manuel Ribes
- , Mitali P. Patel
- & Peter-Christian Klöhn
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Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors
The molecular basis of functional diversity between obligatorily dimeric mGluRs is not understood. The authors show that functional differences typically attributed to differences in the agonist binding pocket emerge from differences between homomeric and heteromeric Group II and III Gi-coupled mGluRs in dimerization interface interactions.
- Chris Habrian
- , Naomi Latorraca
- & Ehud Y. Isacoff
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Immunoproximity biotinylation reveals the axon initial segment proteome
The molecular composition of the axon initial segment (AIS) is not well defined. Here, the authors used a ratiometric immunoproximity labeling strategy on fixed wild-type rat neurons to identify the AIS proteome, including the scaffolding protein SCRIB.
- Wei Zhang
- , Yu Fu
- & Peng Zou
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| Open Access
JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease
It has recently been reported a link between Alzheimer’s disease and mobilization of transposable elements (TEs) in heterochromatic regions. Here the authors demonstrate that dysregulation of the pioneer transcription factor c-JUN (AP-1) underlies aberrant transposable element mobilization, associated innate immune 2 response, and impaired neurogenesis in Alzheimer’s disease.
- Chiara Scopa
- , Samantha M. Barnada
- & Marco Trizzino
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| Open Access
Enhanced 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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CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice
Ceramides in peripheral tissues contribute to obesity-related metabolic dysfunction. This study reveals that CerS6-derived ceramides induce hypothalamic lipotoxicity in mice via altered ER/mitochondrial homeostasis.
- Philipp Hammerschmidt
- , Sophie M. Steculorum
- & Jens C. Brüning
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| Open Access
Fear extinction is regulated by the activity of long noncoding RNAs at the synapse
Synaptic activity controls the extinction of conditioned fear. Here the authors discovered a new way that the brain controls memories of fear: a long noncoding RNA called Gas5 that coordinates the activity of RNA granules in the synaptic compartment.
- Wei-Siang Liau
- , Qiongyi Zhao
- & Timothy W. Bredy
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| Open Access
Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly
The soluble neurotrophic factor GDNF promotes trans-synaptic adhesion through its co-receptor GFRα1. Here, the authors describe the structural basis for GDNF-GFRα1 adhesion and reconstitute assemblies bridging membranes, demonstrating that binding of either the RET receptor or proteoglycans can disrupt this adhesive function.
- F. M. Houghton
- , S. E. Adams
- & N. Q. McDonald
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| Open Access
A 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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| Open Access
CHEX-seq detects single-cell genomic single-stranded DNA with catalytical potential
The in situ single-stranded open chromatin landscape is dynamically regulated in single cells. In their efforts to understand brain cells’ functional dynamics and to complement the other single-cell chromatin approaches, the authors present a method named CHEX-seq (CHromatin EXposed).
- Youtao Lu
- , Jaehee Lee
- & James Eberwine
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| Open Access
Targeted 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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| Open Access
Tau forms synaptic nano-biomolecular condensates controlling the dynamic clustering of recycling synaptic vesicles
Using single-molecule super-resolution microscopy, researchers revealed that Tau controls the recycling pool of synaptic vesicles in hippocampal neurons by forming nanoscale biomolecular condensates that are dynamically regulated by neuronal activity.
- Shanley F. Longfield
- , Mahdie Mollazade
- & Ramón Martínez-Mármol
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Dissecting 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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Antibody-directed extracellular proximity biotinylation reveals that Contactin-1 regulates axo-axonic innervation of axon initial segments
Few resident cell surface proteins have been identified at the axon initial segment. Here, Ogawa and colleagues use proximity labeling and proteomics to identify Contactin-1 as a transmembrane axon initial segment protein that regulates brain wiring.
- Yuki Ogawa
- , Brian C. Lim
- & Matthew N. Rasband
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GSG1L-containing AMPA receptor complexes are defined by their spatiotemporal expression, native interactome and allosteric sites
TARPs and GSG1L are evolutionarily- and structurally-related AMPA receptor auxiliary subunits that differ in function through unresolved mechanisms. Here, the authors provide insight into the spatiotemporal expression, composition, and functionality of GSG1L-containing protein complexes.
- Amanda M. Perozzo
- , Jochen Schwenk
- & Derek Bowie
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| Open Access
Synapsin condensation controls synaptic vesicle sequestering and dynamics
Brain functioning critically relies on coordinated neurotransmitter release by synaptic vesicles (SVs) at synapses. This study shows that synapsin/SVs condensation is sufficient to guarantee reliable confinement and motility of SVs at synapses in vivo.
- Christian Hoffmann
- , Jakob Rentsch
- & Dragomir Milovanovic
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Neural 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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| Open Access
A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus
How the circadian clock generates rhythms of arousal remains unclear. Here, authors show that a clock-output molecule reduces excitability of an arousal circuit during the active phase. These results suggest a multifaceted role for the clock in arousal.
- Qiang Liu
- , Benjamin J. Bell
- & Mark N. Wu
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| Open Access
PIWI-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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| Open Access
Distinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor
Genetically encoded dopamine sensors have emerged as an alternative to voltammetry for in vivo dopamine measurements. Here, the authors compare these two methods directly, and document dopamine responses during Pavlovian conditioning across the striatum.
- Armando G. Salinas
- , Jeong Oen Lee
- & David M. Lovinger
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| Open Access
Prosaposin 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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| Open Access
Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types
Tools for gaining long-term genetic access to mu-opioid receptor (MOR) neural cell types are limited. Here, the authors develop a suite of adeno-associated viral tools allowing selective genetic access to MOR cell types, and showcase their use across species.
- Gregory J. Salimando
- , Sébastien Tremblay
- & Gregory Corder
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| Open Access
Heterogeneous receptor expression underlies non-uniform peptidergic modulation of olfaction in Drosophila
Neuropeptides are ancient modulators of neural signaling, but remain poorly understood. Here, the authors examine the neural and molecular substrates that enable a single neuropeptide to differentially modulate olfactory input to the Drosophila AL.
- Tyler R. Sizemore
- , Julius Jonaitis
- & Andrew M. Dacks
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| Open Access
Human forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways
Identifying schizophrenia risk genes is essential for illuminating the disease etiology. Here, authors prioritized Propionyl-CoA Carboxylase Subunit Beta (PCCB) as a schizophrenia-associated gene, and linked PCCB to GABAergic pathways using human forebrain organoids-based transcriptomic and metabolomic analysis.
- Wendiao Zhang
- , Ming Zhang
- & Qingtuan Meng
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Article
| Open Access
Combinatorial expression of neurexins and LAR-type phosphotyrosine phosphatase receptors instructs assembly of a cerebellar circuit
Whether presynaptic ‘hub’ adhesion molecules are essential for synapse formation is still unclear. Here, the authors generate sextuple conditional knockout mice that target Neurexins and LAR-PTPRs and find that their combinatorial expression instructs the assembly of a cerebellar circuit.
- Alessandra Sclip
- & Thomas C. Südhof
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| Open Access
LINE-1 regulates cortical development by acting as long non-coding RNAs
Here the authors reveal that by acting as non-coding RNAs, L1s are bound by PRC2 and inhibit its activity on genes crucial for regulating proliferation and differentiation in neural progenitor cells.
- Damiano Mangoni
- , Alessandro Simi
- & Stefano Gustincich
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| Open Access
Neurexin-3 subsynaptic densities are spatially distinct from Neurexin-1 and essential for excitatory synapse nanoscale organization in the hippocampus
How do individual neurexins control distinct synaptic properties? Here, the authors show that the nanoscopic properties of Nrxn1 and Nrxn3 are spatially discrete and propose a model where Nrxn1 and Nrxn3 signal in parallel to control synapse function.
- Brian A Lloyd
- , Ying Han
- & Jason Aoto
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Article
| Open Access
Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice
Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE). Here, authors show that the chemogenetic inhibition of GAD2 population in the SNr region, or the targeted overexpression of mitochondrial UCP2 in such population, or systemic application of a mitochondrial-targeting antioxidant drug Mito-Q could effectively ameliorate HE.
- Yunhu Bai
- , Kenan Li
- & Yanling Yang
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| Open Access
Cytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr
The neuronal RNA-binding protein Ptbp2 is known to regulate neuronal differentiation by modulating alternative splicing. Here, the authors reveal an additional role of cytosolic Ptbp2, which regulates axon growth by fine-tuning the mRNA transport and local synthesis of an RNA-binding protein hnRNP R.
- Saeede Salehi
- , Abdolhossein Zare
- & Michael Sendtner
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| Open Access
Blood transcriptomic signatures associated with molecular changes in the brain and clinical outcomes in Parkinson’s disease
Understanding molecular processes behind variable clinical features of Parkinson’s disease is valuable. Distinct molecular patterns in the brains, reflected in the blood, reveal mechanisms linked to clinical diversity in cognitive and motor decline.
- Krithi Irmady
- , Caryn R. Hale
- & Robert B. Darnell
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| Open Access
Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution
The choroid plexus (ChP) modulates cerebrospinal fluid (CSF) composition and the blood-CSF barrier. Here the authors show that the ChP is a critical circadian component with time-of-day variations in translation, barrier, and metabolism to alter CSF composition.
- Ryann M. Fame
- , Peter N. Kalugin
- & Maria K. Lehtinen
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| Open Access
Drosophila motor neuron boutons remodel through membrane blebbing coupled with muscle contraction
Neuronal remodeling is critical for neuronal function. Here, the authors report that motor neurons use membrane blebbing coupled to muscle contraction as a mechanism for synaptic bouton formation, suggesting that mechanical force plays a key role in neuronal remodeling.
- Andreia R. Fernandes
- , João P. Martins
- & Rita O. Teodoro
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| Open Access
Cochlear transcript diversity and its role in auditory functions implied by an otoferlin short isoform
The repertoire of mRNA isoforms in the cochlea remains unknown. Here, authors generated a full-length transcriptome atlas by ScISOr-seq, identified and studied Otof short isoform, extended our understanding of auditory function in isoform resolution.
- Huihui Liu
- , Hongchao Liu
- & Hao Wu
Remodeling of the postsynaptic proteome in male mice and marmosets during synapse development