Accumulation of α-synuclein in dementia with Lewy bodies is associated with decline in the α-synuclein-degrading enzymes kallikrein-6 and calpain-1

Miners, Scott; Renfrew, Ruth; Swirski, Marta; Love, Seth

doi:10.1186/s40478-014-0164-0

Cited by 16 publications

(33 citation statements)

References 57 publications

(84 reference statements)

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“…Supporting the model, several studies have shown the presence of neuropathological thalamic alterations in DLB and PDD along with altered GABAergic and cholinergic receptors and structural and cellular abnormalities of the thalamic nuclei . Interestingly, a recent review extensively analyzed the role of α7 nicotinic receptor activity of TRN neurons in theproduction of DLB hallucinations .…”

Section: Thalamocortical Dysrhythmia As the Driver Of Dmn Decouplingmentioning

confidence: 99%

“…Supporting the model, several studies have shown the presence of neuropathological thalamic alterations in DLB and PDD along with altered GABAergic and cholinergic receptors and structural and cellular abnormalities of the thalamic nuclei. [124][125][126][127][128][129][130][131][132] Interestingly, a recent review extensively analyzed the role of α7 nicotinic receptor activity of TRN neurons in theproduction of DLB hallucinations. 133 Of note, the presence of DMN decoupling along with signs of primary thalamic degeneration has also been observed in frontotemporal dementia patients carrying the C9orf72 mutation, a condition characterized by severe psychosis.…”

Section: Thalamocortical Dysrhythmia As the Driver Of Dmn Decouplingmentioning

confidence: 99%

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Hallucinations, somatic‐functional disorders of PD‐DLB as expressions of thalamic dysfunction

et al. 2019

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Hallucinations, delusions, and functional neurological manifestations (conversion and somatic symptom disorders) of Parkinson's disease (PD) and dementia with Lewy bodies increase in frequency with disease progression, predict the onset of cognitive decline, and eventually blend with and are concealed by dementia. These symptoms share the absence of reality constraints and can be considered comparable elements of the PD‐dementia with Lewy bodies psychosis. We propose that PD‐dementia with Lewy bodies psychotic disorders depend on thalamic dysfunction promoting a theta burst mode and subsequent thalamocortical dysrhythmia with focal cortical coherence to theta electroencephalogram rhythms. This theta electroencephalogram activity, also called fast‐theta or pre‐alpha, has been shown to predict cognitive decline and fluctuations in Parkinson's disease with dementia and dementia with Lewy bodies. These electroencephalogram alterations are now considered a predictive marker for progression to dementia. The resulting thalamocortical dysrhythmia inhibits the frontal attentional network and favors the decoupling of the default mode network. As the default mode network is involved in integration of self‐referential information into conscious perception, unconstrained default mode network activity, as revealed by recent imaging studies, leads to random formation of connections that link strong autobiographical correlates to trivial stimuli, thereby producing hallucinations, delusions, and functional neurological disorders. The thalamocortical dysrhythmia default mode network decoupling hypothesis provides the rationale for the design and testing of novel therapeutic pharmacological and nonpharmacological interventions in the context of PD, PD with dementia, and dementia with Lewy bodies. © 2019 International Parkinson and Movement Disorder Society

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“…Supporting the model, several studies have shown the presence of neuropathological thalamic alterations in DLB and PDD along with altered GABAergic and cholinergic receptors and structural and cellular abnormalities of the thalamic nuclei . Interestingly, a recent review extensively analyzed the role of α7 nicotinic receptor activity of TRN neurons in theproduction of DLB hallucinations .…”

Section: Thalamocortical Dysrhythmia As the Driver Of Dmn Decouplingmentioning

confidence: 99%

“…Supporting the model, several studies have shown the presence of neuropathological thalamic alterations in DLB and PDD along with altered GABAergic and cholinergic receptors and structural and cellular abnormalities of the thalamic nuclei. [124][125][126][127][128][129][130][131][132] Interestingly, a recent review extensively analyzed the role of α7 nicotinic receptor activity of TRN neurons in theproduction of DLB hallucinations. 133 Of note, the presence of DMN decoupling along with signs of primary thalamic degeneration has also been observed in frontotemporal dementia patients carrying the C9orf72 mutation, a condition characterized by severe psychosis.…”

Section: Thalamocortical Dysrhythmia As the Driver Of Dmn Decouplingmentioning

confidence: 99%

Hallucinations, somatic‐functional disorders of PD‐DLB as expressions of thalamic dysfunction

et al. 2019

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“…Extracellular species of both oligomeric and fibrillar α-syn can be internalized and induce intracellular seeding aggregation in cultured cells [6, 15, 16]. Such effects can be potentiated by failure in the proteasomal [17, 18] or lysosomal [19] degradation systems or by reduced levels/activity of intra- and extracellular proteases [20]. Despite the increased knowledge in this field, our understanding of the roles of different α-syn aggregates for the propagation of pathology in Lewy body disorders remains incomplete.…”

Section: Introductionmentioning

confidence: 99%

Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes

et al. 2016

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Parkinson’s disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

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“…α‐syn and α‐syn‐P129 levels were measured by sandwich ELISA in GuHCl‐solubilized brain tissue extracts and SH‐SY5Y cell lysates, as previously described (Miners et al . ,b; Swirski et al . ) For the α‐syn ELISA, a mouse monoclonal anti‐α‐syn antibody (Syn‐1, raised against epitope corresponding to aa 91–99 (Perrin et al .…”

Section: Methodsmentioning

confidence: 99%

“…We reported previously that the levels of CAPN‐1 and KLK6 are reduced in the cingulate cortex in DLB (Miners et al . ).…”

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confidence: 97%

Endothelin‐converting enzymes degrade α‐synuclein and are reduced in dementia with Lewy bodies

Miners

Love

2017

Journal of Neurochemistry

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We have examined the roles of the endothelin-converting enzyme-1 and -2 (ECE-1 and ECE-2) in the homeostasis of α-synuclein (α-syn) and pathogenesis of Lewy body disease. The ECEs are named for their ability to convert inactive big endothelin to the vasoactive peptide endothelin-1 (EDN1). We have found that ECE-1 and ECE-2 cleave and degrade α-syn in vitro and siRNA-mediated knockdown of ECE-1 and ECE-2 in SH-SY5Y neuroblastoma cells significantly increased α-syn both intracellularly (within the cell lysate) (p < 0.05 for both ECE-1 and -2) and extracellularly (in the surrounding medium) (p < 0.05 for ECE-1 and p = 0.07 for ECE-2). Double immunofluorescent labelling showed co-localization of ECE-1 and ECE-2 with α-syn within the endolysosomal system (confirmed by a proximity ligation assay). To assess the possible relevance of these findings to human Lewy body disease, we measured ECE-1 and ECE-2 levels by sandwich ELISA in post-mortem samples of cingulate cortex (a region with a predilection for Lewy body pathology) in dementia with Lewy bodies (DLB) and age-matched controls. ECE-1 (p < 0.001) and ECE-2 (p < 0.01) levels were significantly reduced in DLB and both enzymes correlated inversely with the severity of Lewy body pathology as indicated by the level of α-syn phosphorylated at Ser129 (r = -0.54, p < 0.01 for ECE-1 and r = -0.49, p < 0.05 for ECE-2). Our novel findings suggest a role for ECEs in the metabolism of α-syn that could contribute to the development and progression of DLB.

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Accumulation of α-synuclein in dementia with Lewy bodies is associated with decline in the α-synuclein-degrading enzymes kallikrein-6 and calpain-1

Cited by 16 publications

References 57 publications

Hallucinations, somatic‐functional disorders of PD‐DLB as expressions of thalamic dysfunction

Hallucinations, somatic‐functional disorders of PD‐DLB as expressions of thalamic dysfunction

Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes

Endothelin‐converting enzymes degrade α‐synuclein and are reduced in dementia with Lewy bodies

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