Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo

Wu, Qihui; Shaikh, Muhammad A.; Meymand, Emily S.; Zhang, Bin; Luk, Kelvin C.; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1007/s00401-020-02227-6

Cited by 43 publications

(55 citation statements)

References 70 publications

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“…The existence of the main component of Lewy bodies, α-synuclein, is the main pathological change observed in PD. [2,15] Following TVC treatment, the expression of α-synuclein and its corresponding genes were significantly improved compared to that in other groups (Figure 2D,E). Activation of the LRRK2 protein kinase is closely related to PD, but it cannot be directly measured.…”

Section: (7 Of 13)mentioning

confidence: 95%

“…Significant pathological changes in PD include the loss of substantia nigra neurons and abnormal accumulation of Lewy bodies. [2] At present, the With the development of nanotechnology, nanomaterials have shown great potential in many fields. Among them, tetrahedral framework nucleic acid (TFNA) is a new type of nanoparticle with excellent biocompatibility and biosafety, and the penetration of the BBB can be achieved without the aid of a carrier.…”

Section: Introductionmentioning

confidence: 99%

“…Significant pathological changes in PD include the loss of substantia nigra neurons and abnormal accumulation of Lewy bodies. [ 2 ] At present, the main clinical treatments are dopamine (DA) drug therapy and surgical deep brain electrical stimulation, which are collectively referred to as symptomatic treatments. However, these approaches can only improve the symptoms of PD and cannot prevent the progression of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Treating LRRK2‐Related Parkinson's Disease by Inhibiting the mTOR Signaling Pathway to Restore Autophagy

Cui

Yang

Chen

et al. 2021

Adv Funct Materials

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Parkinson's disease (PD) is the most common chronic neurodegenerative disease and is characterized by motor dysfunctions. Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are a major cause of the neurotoxicity that causes PD. As an inhibitor of LRRK2 activity, vitamin B12 (VB12) is a promising therapeutic option for PD and is shown to restore autophagy in PD models. However, the dependence on transporters and the extremely low brain tissue utilization of VB12 limit its therapeutic effects. Based on this, VB12-loaded tetrahedral framework nucleic acid (TVC) is synthesized and its effectiveness in the model of PD induced with 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine is evaluated. TVC provides better recovery of autophagy than free VB12 did both in vivo and in vitro, leading to enhanced clearing of abnormal protein accumulations and restoration of PD motor symptoms. It is believed that TVC has broad therapeutic potential in the treatment of PD and similar neurodegenerative diseases.

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Section: (7 Of 13)mentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treating LRRK2‐Related Parkinson's Disease by Inhibiting the mTOR Signaling Pathway to Restore Autophagy

Cui

Yang

Chen

et al. 2021

Adv Funct Materials

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“…When adding PFFs into cultured hippocampal neurons, they compromised synaptic miniature EPSC firing frequency, inhibited spines formation, along with decreased action potential firing rate [40], where another group observed paradoxical functional defects induced by Syn PFFs [41]. On the other hand, the neuronal hyperactivity promoted the secretion of Syn into extracellular in vivo as well as in vitro [42], thus facilitated the propagation of pathology in CNS, and this was confirmed by an ex vivo slice culture system recently [33]. The activity-dependent regulation of protein aggregation and spreading also applies to tau and Aβ in AD animal models [43][44].…”

Section: Pathophysiological Functions Of -Synuclein In Pdmentioning

confidence: 93%

“…Since human brains are valuable resources and are not available in every institute, people are seeking alternative options that could recruit pathological inclusions in wild-type tissues or in vivo. About 10 years ago, recombinant Syn monomers were reported to spontaneously aggregate into the preformed fibrils (PFFs) and induce Syn inclusions in wild-type primary cultured hippocampal neurons and in vivo [28,32], as well as in slice cultures recently [33], which mimics the pathogenesis of PD in human brains. When self-template-dependent amplification for several rounds, these amyloidogenic PFF 'seeds' not only recruit endogenous Syn but also recruit tau into aggregates both in vitro and in vivo [34].…”

Section: Pathophysiological Functions Of -Synuclein In Pdmentioning

confidence: 99%

Revisit the Cellular Transmission and Emerging Techniques in Proteinopathies

Jiang¹,

Liu²,

Wu³

2021

Preprint

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Alzheimer’s and Parkinson's diseases (AD and PD) are amongst top of the prevalent neurodegenerative disease. One-third of PD patients are diagnosed with dementia, a pre-symptom of AD, but the underlying mechanism is elusive. Amyloid beta (Aβ) and α-synuclein are two of the most investigated proteins, whose pathological aggregation and spreading are crucial to the pathogenesis of AD and PD, respectively. Transcriptomic studies of the mammalian central nervous system shed light on gene expression profiles at molecular levels, regarding the complexity of neuronal morphologies and electrophysiological inputs/outputs. In the last decade, the booming of the single-cell RNA sequencing technique helped to understand gene expression patterns, alternative splicing, novel transcripts, and signal pathways in the nervous system at single-cell levels, providing insight for molecular taxonomy and mechanistic targets of the degenerative nervous system. Here, we re-visited the cell-cell transmission mechanisms of Aβ and α-synuclein in medi-ating disease propagation, and summarized recent single-cell transcriptome sequencing from different perspectives and discussed its understanding of neurodegenerative diseases.

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Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

et al. 2023

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Background The intercellular transmission of pathogenic proteins plays a crucial role in the progression of neurodegenerative diseases. Previous research has shown that the neuronal uptake of such proteins is activity‐dependent; however, the detailed mechanisms underlying activity‐dependent α‐synuclein transmission in Parkinson's disease remain unclear. Objective To examine whether α‐synuclein transmission is affected by Ca2+–calmodulin–calcineurin signaling in cultured cells and mouse models of Parkinson's disease. Methods Mouse primary hippocampal neurons were used to examine the effects of the modulation of Ca2+–calmodulin–calcineurin signaling on the neuronal uptake of α‐synuclein preformed fibrils. The effects of modulating Ca2+–calmodulin–calcineurin signaling on the development of α‐synuclein pathology were examined using a mouse model injected with α‐synuclein preformed fibrils. Results Modulation of Ca2+–calmodulin–calcineurin signaling by inhibiting voltage‐gated Ca2+ channels, calmodulin, and calcineurin blocked the neuronal uptake of α‐synuclein preformed fibrils via macropinocytosis. Different subtypes of voltage‐gated Ca2+ channel differentially contributed to the neuronal uptake of α‐synuclein preformed fibrils. In wild‐type mice inoculated with α‐synuclein preformed fibrils, we found that inhibiting calcineurin ameliorated the development of α‐synuclein pathology. Conclusion Our data suggest that Ca2+–calmodulin–calcineurin signaling modulates α‐synuclein transmission and has potential as a therapeutic target for Parkinson's disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo

Cited by 43 publications

References 70 publications

Treating LRRK2‐Related Parkinson's Disease by Inhibiting the mTOR Signaling Pathway to Restore Autophagy

Treating LRRK2‐Related Parkinson's Disease by Inhibiting the mTOR Signaling Pathway to Restore Autophagy

Revisit the Cellular Transmission and Emerging Techniques in Proteinopathies

Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

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Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo

Cited by 43 publications

References 70 publications

Treating LRRK2‐Related Parkinson's Disease by Inhibiting the mTOR Signaling Pathway to Restore Autophagy

Treating LRRK2‐Related Parkinson's Disease by Inhibiting the mTOR Signaling Pathway to Restore Autophagy

Revisit the Cellular Transmission and Emerging Techniques in Proteinopathies

Ca2+–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

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Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission