Alpha-synuclein aggregates are excluded from calbindin-D28k-positive neurons in dementia with Lewy bodies and a unilateral rotenone mouse model

Rcom-H'cheo-Gauthier, Alexandre Nay; Davis, Amelia; Meedeniya, Adrian Cuda Banda; Pountney, Dean L.

doi:10.1016/j.mcn.2016.10.003

Cited by 16 publications

(15 citation statements)

References 43 publications

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“…Moreover, a recent study has described the over-representation of CB-positive (CB+) neurons in DLB, and the almost complete exclusion of α-syn aggregates in CB+ neurons. This study draws the same conclusions in a rotenone (oxidative stress) mouse model of α-synucleopathy (Rcom-H'cheo-Gauthier et al, 2016). In both DLB and the mouse model, occasional neurons with low CB expression showed small α-syn aggregates, but large perinuclear inclusion bodies were only detected in CB- cells (Figure 1B; Rcom-H'cheo-Gauthier et al, 2016).…”

Section: Ca(ii) Regulation In Ageing and Neurodegenerationsupporting

confidence: 78%

“…More recently, α-syn aggregation was studied using an oxidative stress mouse model where unilateral lesion was performed using the mitochondrial complex I inhibitor, rotenone. The results showed an increase in α-syn aggregates in the lesioned hemisphere, compared to sham or unlesioned, especially in aged animals, combined with an exclusion of α-syn aggregates from CB-expressing neurons, further implicating a cooperative interaction between calcium buffering and oxidative stress (Rcom-H'cheo-Gauthier et al, 2016). …”

Section: Oxidative Stress and α-Synuclein Oligomerizationmentioning

confidence: 92%

“…Parkinson's disease linked point mutations are indicated within the neurotransmitter vesicle binding domain. (B) Neuronal Calbindin-D28K (CB), inhibits α-syn inclusion bodies in DLB and mouse model tissue (Rcom-H'cheo-Gauthier et al, 2016). (B1-2) Dementia with Lewy bodies immunofluorescence for α-syn (green) and CB (red, arrow) showing rare, small cytoplasmic α-syn aggregates (arrowhead) in a CB+ neuron and a typical, large perinuclear α-syn inclusion body in a CB- neuron.…”

Section: Introduction: α-Synuclein In Neurodegenerationmentioning

confidence: 99%

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Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies

et al. 2016

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Aggregation of the pre-synaptic protein, α-synuclein (α-syn), is the key etiological factor in Parkinson's disease (PD) and other alpha-synucleinopathies, such as multiple system atrophy (MSA) and Dementia with Lewy bodies (DLB). Various triggers for pathological α-syn aggregation have been elucidated, including post-translational modifications, oxidative stress, and binding of metal ions, such as calcium. Raised neuronal calcium levels in PD may occur due to mitochondrial dysfunction and/or may relate to calcium channel dysregulation or the reduced expression of the neuronal calcium buffering protein, calbindin-D28k. Recent results on human tissue and a mouse oxidative stress model show that neuronal calbindin-D28k expression excludes α-syn inclusion bodies. Previously, cell culture model studies have shown that transient increases of intracellular free Ca(II), such as by opening of the voltage-gated plasma calcium channels, could induce cytoplasmic aggregates of α-syn. Raised intracellular free calcium and oxidative stress also act cooperatively to promote α-syn aggregation. The association between raised neuronal calcium, α-syn aggregation, oxidative stress, and neurotoxicity is reviewed in the context of neurodegenerative α-syn disease and potential mechanism-based therapies.

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Section: Ca(ii) Regulation In Ageing and Neurodegenerationsupporting

confidence: 78%

Section: Oxidative Stress and α-Synuclein Oligomerizationmentioning

confidence: 92%

Section: Introduction: α-Synuclein In Neurodegenerationmentioning

confidence: 99%

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Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies

et al. 2016

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“…Calcium ions can trigger AS aggregation in vitro , even at low micromolar concentrations, and thus, it has been proposed that Ca(II) might induce cytoplasmic AS aggregates in cells (Nath et al ; Follett et al ; Rcom‐H’cheo‐Gauthier et al ). Accordingly, the study of AS‐Ca(II) interactions and their role in protein aggregation and Parkinson’s disease became an active area of research in the last years (Rcom‐H’cheo‐Gauthier et al ; Zaichick et al ). Here we summarized the most important recent findings.…”

Section: α‐Synuclein Is a Metal‐binding Proteinmentioning

confidence: 99%

Effects of alpha‐synuclein post‐translational modifications on metal binding

González

Arcos-López

König

et al. 2019

Journal of Neurochemistry

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Parkinson’s disease is the second most common neurodegenerative disorder worldwide. Neurodegeneration in this pathology is characterized by the loss of dopaminergic neurons in the substantia nigra, coupled with cytoplasmic inclusions known as Lewy bodies containing α‐synuclein. The brain is an organ that concentrates metal ions, and there is emerging evidence that a break‐down in metal homeostasis may be a critical factor in a variety of neurodegenerative diseases. α‐synuclein has emerged as an important metal‐binding protein in the brain, whereas these interactions play an important role in its aggregation and might represent a link between protein aggregation, oxidative damage, and neuronal cell loss. Additionally, α‐synuclein undergoes several post‐translational modifications that regulate its structure and physiological function, and may be linked to the aggregation and/or oligomer formation. This review is focused on the interaction of this protein with physiologically relevant metal ions, highlighting the cases where metal‐AS interactions profile as key modulators for its structural, aggregation, and membrane‐binding properties. The impact of α‐synuclein phosphorylation and N‐terminal acetylation in the metal‐binding properties of the protein are also discussed, underscoring a potential interplay between PTMs and metal ion binding in regulating α‐synuclein physiological functions and its role in pathology. This article is part of the Special Issue “Synuclein”.

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“…Reduced expression of Ca 2+ -buffering proteins, as well as a chronic increase in intracellular Ca 2+ in aging SNc DA neurons, are likely to be mechanisms that contribute to the mitochondrial and ER stress observed in PD. Mice overexpressing calbindin-D28k are resistant to the toxic effects of MPTP and to α-synuclein aggregation (Rcom-H'cheo-Gauthier et al, 2016; Yuan et al, 2013), establishing a causal link between buffering Ca 2+ and protection against cell death. Interestingly, calbindin-D28k is also a reported risk factor for sporadic forms of PD in a Japanese population (Mizuta et al, 2008; Soto-Ortolaza et al, 2010).…”

Section: Cytosolic Ca2+ Buffering and Pdmentioning

confidence: 99%

The role of Ca2+ signaling in Parkinson's disease

Zaichick

McGrath

Caraveo

2017

Disease Models &Amp; Mechanisms

158

101

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Across all kingdoms in the tree of life, calcium (Ca2+) is an essential element used by cells to respond and adapt to constantly changing environments. In multicellular organisms, it plays fundamental roles during fertilization, development and adulthood. The inability of cells to regulate Ca2+ can lead to pathological conditions that ultimately culminate in cell death. One such pathological condition is manifested in Parkinson's disease, the second most common neurological disorder in humans, which is characterized by the aggregation of the protein, α-synuclein. This Review discusses current evidence that implicates Ca2+ in the pathogenesis of Parkinson's disease. Understanding the mechanisms by which Ca2+ signaling contributes to the progression of this disease will be crucial for the development of effective therapies to combat this devastating neurological condition.

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Alpha-synuclein aggregates are excluded from calbindin-D28k-positive neurons in dementia with Lewy bodies and a unilateral rotenone mouse model

Cited by 16 publications

References 43 publications

Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies

Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies

Effects of alpha‐synuclein post‐translational modifications on metal binding

The role of Ca2+ signaling in Parkinson's disease

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