Molecular basis of astrocyte diversity and morphology across the CNS in health and disease

Science, Journal Year: 2022, Volume and Issue: 378(6619)

Published: Nov. 3, 2022

Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, morphology across the mouse central nervous system (CNS). We identified shared region-specific astrocytic genes functions explored cellular origins their regional diversity. gene networks correlated with morphology, several which unexpectedly contained Alzheimer’s disease (AD) risk genes. CRISPR/Cas9–mediated reduction candidate reduced morphological complexity resulted in cognitive deficits. The same were down-regulated human AD, an AD model that displayed other brain disorders. thus provide comprehensive data on diversity mechanisms CNS basis health disease.

Language: Английский

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Cellular origins of dsRNA, their recognition and consequences

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 23(4), P. 286 - 301

Published: Nov. 23, 2021

Language: Английский

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Single-cell dissection of the human brain vasculature

Nature, Journal Year: 2022, Volume and Issue: 603(7903), P. 893 - 899

Published: Feb. 14, 2022

Language: Английский

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Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Life, Journal Year: 2021, Volume and Issue: 11(1), P. 69 - 69

Published: Jan. 19, 2021

The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In eukaryotic system, TCA occurs completely mitochondria, while intermediates are retained inside mitochondria due their polarity hydrophilicity. Under cell stress conditions, can become disrupted release contents, which act as danger signals cytosol. Of note, may also leak dysfunctioning regulate cellular processes. Increasing evidence shows that metabolites substantially involved regulation immune responses. this review, we aimed provide comprehensive systematic overview molecular mechanisms each intermediate play key roles regulating immunity discuss its implication for activation suppression.

Language: Английский

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Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells

Neuron, Journal Year: 2022, Volume and Issue: 110(16), P. 2607 - 2624.e8

Published: June 28, 2022

Language: Английский

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Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons

Neuron, Journal Year: 2022, Volume and Issue: 110(6), P. 967 - 976.e8

Published: Jan. 19, 2022

Language: Английский

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lncRNA NEAT1: Key player in neurodegenerative diseases

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 86, P. 101878 - 101878

Published: Feb. 3, 2023

Neurodegenerative diseases are the most common causes of disability worldwide. Given their high prevalence, devastating symptoms, and lack definitive diagnostic tests, there is an urgent need to identify potential biomarkers new therapeutic targets. Long non-coding RNAs (lncRNAs) have recently emerged as powerful regulatory molecules in neurodegenerative diseases. Among them, lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported be upregulated Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), amyotrophic lateral sclerosis (ALS). However, whether this part a protective or harmful mechanism still unclear. This review summarizes our current knowledge role NEAT1 its association with characteristic aggregation misfolded proteins: amyloid-β tau AD, α-synuclein PD, mutant huntingtin HD, TAR DNA-binding protein-43 fused sarcoma/translocated liposarcoma ALS. The aim stimulate further research on more precise effective treatments for

Language: Английский

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Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(11), P. 2866 - 2884

Published: Oct. 9, 2023

Abstract Huntington’s disease (HD) is a devastating monogenic neurodegenerative characterized by early, selective pathology in the basal ganglia despite ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to development early cognitive phenotypes are poorly understood. Here we show that there loss synaptic connections between cortex striatum postmortem tissue from patients with HD associated increased activation localization complement proteins, innate immune molecules, elements. We also found levels secreted molecules elevated cerebrospinal fluid premanifest correlate established measures burden. In preclinical genetic models HD, proteins mediate elimination corticostriatal synapses at an stage pathogenesis, marking them for removal microglia, brain’s resident macrophage population. This process requires huntingtin be expressed both cortical striatal neurons. Inhibition complement-dependent mechanism through administration therapeutically relevant C1q function-blocking antibody or ablation receptor on microglia prevented synapse loss, excitatory input rescued visual discrimination learning flexibility deficits models. Together, our findings implicate cascade selective, presymptomatic HD; they provide new data support as therapeutic target intervention.

Language: Английский

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Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(3), P. 383 - 394

Published: Jan. 30, 2024

Abstract Brain region-specific degeneration and somatic expansions of the mutant Huntingtin ( mHTT ) CAG tract are key features Huntington’s disease (HD). However, relationships among expansions, death specific cell types molecular events associated with these processes not established. Here, we used fluorescence-activated nuclear sorting (FANS) deep profiling to gain insight into properties human striatum cerebellum in HD control donors. arise at striatal medium spiny neurons (MSNs), cholinergic interneurons cerebellar Purkinje neurons, ATXN3 MSNs from SCA3 higher levels MSH2 MSH3 (forming MutSβ), which can inhibit nucleolytic excision slip-outs by FAN1. Our data support a model necessary but may be sufficient for identify transcriptional changes toxicity.

Language: Английский

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From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 13021 - 13021

Published: Aug. 21, 2023

Huntington’s disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as highly penetrant dominant likely acting through toxic gain of function mutant protein. Widespread cellular degeneration medium spiny neurons caudate nucleus and putamen are responsible for onset symptomology that encompasses motor, cognitive, behavioural abnormalities. Over past 150 years research since George Huntington published his description, plethora pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption proteostasis, transcriptional dysregulation, neuroinflammation. Despite identification characterisation causative gene mutation significant advances our understanding pathology recent years, disease-modifying intervention has not yet clinically approved. This review includes overview disease, from its aetiology to clinical presentation manifestation. An updated view molecular latest therapeutic developments will also be discussed.

Language: Английский

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