α-Synuclein modulates tau spreading in mouse brains DOI Creative Commons

Fares Bassil,

Emily S. Meymand, Hannah J. Brown

et al.

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 218(1)

Published: July 25, 2020

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) Alzheimer's (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate interactions pathological α-syn tau, we sought to model interactions. We show that increased accumulation occur following simultaneous introduction mousepreformed fibrils (mpffs) AD lysate-derived seeds (AD-tau) vitro vivo. Interestingly, absence endogenous mouse mice reduces spreading while did not affect seeding or capacity α-syn. These vivo results consistent our data wherein presence has no synergistic effects on Our point important role as a modulator pathology burden brains AD, PDD, DLB patients.

Language: Английский

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies DOI Creative Commons
Inês Caldeira Brás, Tiago F. Outeiro

Cells, Journal Year: 2021, Volume and Issue: 10(2), P. 375 - 375

Published: Feb. 12, 2021

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. stereotypical distribution and evolution pathology during often attributed cell-to-cell transmission aSyn between interconnected brain regions. spreading conformationally distinct protein assemblies, commonly referred strains, thought result in variety clinically pathologically heterogenous diseases known synucleinopathies. Although tremendous progress has been made field, mechanisms involved transfer these assemblies neural networks their role driving PD progression are still unclear. Here, we present an update relevant discoveries supporting or challenging prion-like hypothesis. We also discuss importance strains various putative molecular release. Understanding pathways underlying propagation will contribute determining etiology related synucleinopathies but assist development new therapeutic strategies.

Language: Английский

Citations

94
Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia DOI Creative Commons
Dorit Trudler, Kristopher L. Nazor, Yvonne S. Eisele

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(15)

Published: April 8, 2021

Significance Release of oligomeric/fibrillar α-synuclein (αSyn) from damaged neurons contributes to neuronal cell death in Parkinson’s disease and other neurodegenerative disorders part via microglial activation. Here, we show that αSyn activates the NLRP3 inflammasome human induced pluripotent stem (hiPSC)-derived microglia (hiMG) dual stimulation involving TLR2 engagement mitochondrial damage. Oligomerized amyloid-β peptide (Aβ), as found Alzheimer’s brains, exacerbates this neuroinflammation. Importantly, misfolded proteins such Aβ, when bound antibody presented hiMG, result enhanced proinflammatory response inflammasome. These findings may have important implications for therapies aimed at depleting misfolded/aggregated brain, they paradoxically trigger neuroinflammation microglia.

Language: Английский

Citations

91
α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss DOI Creative Commons
Dorit Trudler,

Sara Sanz‐Blasco,

Yvonne S. Eisele

et al.

Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 41(10), P. 2264 - 2273

Published: Jan. 22, 2021

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form Lewy bodies, comprised mainly α-synuclein (αSyn), associated with disease progression, have also been linked to other neurodegenerative diseases, including body dementia, Alzheimer's disease, frontotemporal dementia. However, effects αSyn its mechanism synaptic damage remain incompletely understood. Here, we show that oligomers induce Ca 2+ -dependent release glutamate from astrocytes obtained male female mice, mice overexpressing manifest increased tonic vivo . In turn, this extracellular activates receptors, extrasynaptic NMDARs (eNMDARs), on neurons both culture hippocampal slices αSyn-overexpressing mice. Additionally, patch-clamp recording outside-out patches, found oligomerized can directly activate eNMDARs. organotypic slices, oligomeric induces eNMDAR-mediated loss, which be reversed by drug NitroSynapsin. When expose human induced pluripotent stem cell-derived cerebrocortical αSyn, find similar effects. Importantly, improved NMDAR antagonist NitroSynapsin, selectively inhibits over physiological activity, protects synapses αSyn-induced our model systems, thus meriting further study for therapeutic potential. SIGNIFICANCE STATEMENT Loss function ensuing progression (PD), dementia (LBD), diseases. remains α-Synuclein (αSyn) misfolds PD/LBD, forming bodies contributing pathogenesis. misfolded/oligomeric releases excessive astrocytic glutamate, turn activating NMDA receptors thereby damage. eNMDARs, While FDA-approved memantine has reported offer some benefit PD/LBD (Hershey Coleman-Jackson, 2019), eNMDAR NitroSynapsin ameliorates spine providing potential disease-modifying intervention PD/LBD.

Language: Английский

Citations

82
Mitochondrial Dynamics: A Key Role in Neurodegeneration and a Potential Target for Neurodegenerative Disease DOI Creative Commons

Danying Yang,

Jun Ying,

Xifeng Wang

et al.

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: April 12, 2021

In neurodegenerative diseases, neurodegeneration has been related to several mitochondrial dynamics imbalances such as excessive fragmentation of mitochondria, impaired mitophagy, and blocked mitochondria transport in axons. Mitochondria are dynamic organelles, essential for energy conversion, neuron survival, cell death. As have a significant influence on homeostasis, this review, we mainly discuss the role diseases. There is evidence that dynamics-associated proteins, well pathways, roles pathological process diseases with an impact functions metabolism. However, specific mechanisms need be better understood order propose new therapeutic strategies targeting shown promise recent studies.

Language: Английский

Citations

79
α-Synuclein modulates tau spreading in mouse brains DOI Creative Commons

Fares Bassil,

Emily S. Meymand, Hannah J. Brown

et al.

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 218(1)

Published: July 25, 2020

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) Alzheimer's (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate interactions pathological α-syn tau, we sought to model interactions. We show that increased accumulation occur following simultaneous introduction mousepreformed fibrils (mpffs) AD lysate-derived seeds (AD-tau) vitro vivo. Interestingly, absence endogenous mouse mice reduces spreading while did not affect seeding or capacity α-syn. These vivo results consistent our data wherein presence has no synergistic effects on Our point important role as a modulator pathology burden brains AD, PDD, DLB patients.

Language: Английский

Citations

73