Glymphatic failure as a final common pathway to dementia

Science, Journal Year: 2020, Volume and Issue: 370(6512), P. 50 - 56

Published: Oct. 2, 2020

Sleep is evolutionarily conserved across all species, and impaired sleep a common trait of the diseased brain. quality decreases as we age, disruption regular architecture frequent antecedent to onset dementia in neurodegenerative diseases. The glymphatic system, which clears brain protein waste products, mostly active during sleep. Yet system degrades with suggesting causal relationship between disturbance symptomatic progression dementias. ties that bind sleep, aging, clearance, aggregation have shed new light on pathogenesis broad range diseases, for failure may constitute therapeutically targetable final pathway.

Language: Английский

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Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(3)

Published: March 1, 2023

Abstract Although the discovery of critical role α-synuclein (α-syn) in pathogenesis Parkinson’s disease (PD) is now twenty-five years old, it still represents a milestone PD research. Abnormal forms α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, alteration calcium homeostasis not only but also other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, REM sleep behavior disorder. Furthermore, α-syn-dependent early synaptic plastic alterations underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, presence inflammation experimental models patients, occurring before deposition spreading α-syn, suggests mechanistic link between dysfunction. The knowledge these seminal importance to support research on reliable biomarkers precociously identify possible disease-modifying therapies targeting α-syn. this review, we will discuss issues, providing state art protein synucleinopathies.

Language: Английский

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Mechanisms of secretion and spreading of pathological tau protein

Cellular and Molecular Life Sciences, Journal Year: 2019, Volume and Issue: 77(9), P. 1721 - 1744

Published: Oct. 30, 2019

Abstract Accumulation of misfolded and aggregated forms tau protein in the brain is a neuropathological hallmark tauopathies, such as Alzheimer’s disease frontotemporal lobar degeneration. Tau aggregates have ability to transfer from one cell another induce templated misfolding aggregation healthy molecules previously cells, thereby propagating pathology across different areas prion-like manner. The molecular mechanisms involved cell-to-cell are diverse, not mutually exclusive only partially understood. Intracellular accumulation induces several that aim reduce cellular burden proteins also promote secretion aggregates. However, may be released cells physiologically unrelated aggregation. involves multiple vesicular non-vesicle-mediated pathways, including directly through plasma membrane. Consequently, extracellular can found various forms, both free vesicles, exosomes ectosomes. Once space, internalized by neighboring neurons glial via endocytic, pinocytic phagocytic mechanisms. Importantly, accumulating evidence suggests propagation could provide general mechanism for progression tauopathies other related neurodegenerative diseases. Here, we review recent literature on tau, with particular focus secretion.

Language: Английский

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The α-Synuclein Origin and Connectome Model (SOC Model) of Parkinson’s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

Journal of Parkinson s Disease, Journal Year: 2021, Volume and Issue: 11(2), P. 455 - 474

Published: March 2, 2021

A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects α-synuclein pathobiology that impact course for each patient: anatomical location initial inclusion, propagation dependent on ipsilateral connections dominate connectivity human brain. In some patients, pathology occurs within CNS, leading to a brain-first subtype PD. others, begins in peripheral autonomic nervous system, body-first subtype. cases, it proposed first appears unilaterally, often amygdala. If depends connection strength, unilateral focus will disseminate more hemisphere. Thus, spreads mainly structures including substantia nigra. The asymmetric distribution leads dopaminergic degeneration motor asymmetry. ascends via vagus both left right dorsal nuclei owing overlapping parasympathetic innervation gut. Consequently, inside CNS symmetric, which promotes symmetric brainstem, less At diagnosis, patients already have larger, burden pathology, turn faster progression accelerated cognitive decline. SOC supported by considerable body existing evidence may improved explanatory power.

Language: Английский

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Standardizing workflows in imaging transcriptomics with the abagen toolbox

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Nov. 16, 2021

Gene expression fundamentally shapes the structural and functional architecture of human brain. Open-access transcriptomic datasets like Allen Human Brain Atlas provide an unprecedented ability to examine these mechanisms in vivo; however, a lack standardization across research groups has given rise myriad processing pipelines for using data. Here, we develop abagen toolbox, open-access software package working with data, use it how methodological variability influences outcomes Atlas. Applying three prototypical analyses outputs 750,000 unique pipelines, find that choice pipeline large impact on findings, parameters commonly varied literature influencing correlations between derived gene other imaging phenotypes by as much ρ ≥ 1.0. Our results further reveal ordering parameter importance, steps influence normalization yielding greatest downstream statistical inferences conclusions. The presented work development toolbox lay foundation more standardized systematic transcriptomics, will help advance future understanding

Language: Английский

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Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease

Neuron, Journal Year: 2022, Volume and Issue: 110(15), P. 2422 - 2437.e9

Published: June 1, 2022

Language: Английский

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Liquid-liquid Phase Separation of α-Synuclein: A New Mechanistic Insight for α-Synuclein Aggregation Associated with Parkinson's Disease Pathogenesis

Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 435(1), P. 167713 - 167713

Published: July 3, 2022

Language: Английский

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Connectome-based modelling of neurodegenerative diseases: towards precision medicine and mechanistic insight

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(10), P. 620 - 639

Published: Aug. 24, 2023

Language: Английский

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Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies

Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(3)

Published: March 1, 2022

Abstract Protein misfolding is a general hallmark of protein deposition diseases, such as Alzheimer’s disease or Parkinson’s disease, in which different types aggregated species (oligomers, protofibrils and fibrils) are generated by the cells. Despite widespread interest, relationship between oligomers fibrils aggregation process spreading remains elusive. A large variety experimental evidences supported idea that soluble oligomeric proteins might be more toxic than larger fibrillar forms. Furthermore, lack correlation presence typical pathological inclusions sustained this debate. However, recent data show β-sheet core α-Synuclein (αSyn) unable to establish persistent interactions with lipid bilayers, but they can release responsible for an immediate dysfunction recipient neurons. Reversibly, could also contribute pathogenesis via neuron-to-neuron their direct cell-to-cell transfer generating new fibrils, following neuronal uptake. In Review, we discuss various mechanisms cellular caused αSyn, including oligomer toxicity, fibril toxicity spreading.

Language: Английский

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Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 10, 2022

Abstract Numerous brain disorders demonstrate structural abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these connectomic vulnerabilities remain unknown, has yet be studied in a single multi-disorder framework. Using MRI morphometry the ENIGMA consortium, we construct maps cortical abnormalities for thirteen neurodevelopmental, neurological, psychiatric N = 21,000 participants 26,000 controls, collected using harmonised processing protocol. We systematically compare multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, myelination (molecular vulnerability), as well global measures number connections, centrality, connection diversity (connectomic vulnerability). find relationship between vulnerability white-matter architecture that drives disorder profiles. Local attributes, particularly receptor profiles, constitute best predictors both disorder-specific morphology cross-disorder similarity. Finally, consistently subtended by small subset network epicentres bilateral sensory-motor, inferior temporal lobe, precuneus, superior parietal cortex. Collectively, our results highlight how local attributes connectivity jointly shape abnormalities.

Language: Английский

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