Calcium-Binding Proteins as Determinants of Central Nervous System Neuronal Vulnerability to Disease

Fairless, Richard; Williams, Sarah K.; Diem, Ricarda

doi:10.3390/ijms20092146

Cited by 76 publications

(67 citation statements)

References 111 publications

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“…It was reported that the expression of CBPs in general is very low in case of SNc neurons (Chung et al, 2005;Greene et al, 2005;Mendez et al, 2005) and reduces even further under PD (Fairless et al, 2019;Hurley et al, 2013;Yamada et al, 1990;Zaichick et al, 2017).…”

Section: Enhancement Of Cbp Expressionmentioning

confidence: 99%

A Multi-Scale Computational Model of Excitotoxic Loss of Dopaminergic Cells in Parkinson’s Disease

Muddapu

Chakravarthy

2020

Preprint

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Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons in Substantia Nigra pars compacta (SNc). Although the exact cause of the cell death is not clear, the hypothesis that metabolic deficiency is a key facor has been gaining attention in the recent years. In the present study, we investigate this hypothesis using a multi-scale computational model of the subsystem of the basal ganglia comprising Subthalamic Nucleus (STN), Globus Pallidus externa (GPe) and SNc. The model is a multiscale model in that interactions among the three nuclei are simulated using more abstract Izhikevich neuron models, while the molecular pathways involved in cell death of SNc neurons are simulated in terms of detailed chemical kinetics. Simulation results obtained from the proposed model showed that energy deficiencies occurring at cellular and network levels could precipitate the excitotoxic loss of SNc neurons in PD. At the subcellular level, the models show how calcium elevation leads to apoptosis of SNc neurons. The therapeutic effects of several neuroprotective interventions are also simulated in the model. From neuroprotective studies, it was clear that glutamate inhibition and apoptotic signal blocker therapies were able to halt the progression of SNc cell loss when compared to other therapeutic interventions, which only slows down the progression of SNc cell loss. Deficiency Izhikevich (Spiking) Neuronal Model (STN, GPe) The Izhikevich neuronal models are capable of exhibiting biologically realistic firing patterns, at a relatively low computational expense (Izhikevich, 2003). The proposed model of HEM consists of GPe and STN neurons are modeled as Izhikevich spiking neuron model, where the Izhikevich parameters are adopted from the literature (Mandali et al., 2015;Michmizos and Nikita, 2011). Based on the anatomical data of rat basal ganglia, the neuronal population sizes in the model are selected (Arbuthnott and Wickens, 2007;Oorschot, 1996).The external bias current ( ) was adjusted to match the firing rate of nuclei with published data (Tripathy et al., 2015).

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Section: Enhancement Of Cbp Expressionmentioning

confidence: 99%

A Multi-Scale Computational Model of Excitotoxic Loss of Dopaminergic Cells in Parkinson’s Disease

Muddapu

Chakravarthy

2020

Preprint

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“…Parvalbumin itself as a calcium-binding protein is believed to serve the distinct function of buffering intracellular Ca 2+ , enabling the neuron to fire rapid spike trains and protecting it from toxic intracellular calcium levels (Fairless et al, 2019;Ferguson and Gao, 2018). This might support the unique function of this neuronal subtype: parvalbumin positive interneurons are known for their remarkable fast spiking phenotype with a local widespread of activity regulating contacts to nearly every pyramidal neuron in their surrounding (Ferguson and Gao, 2018;Kawaguchi, 1997;Packer and Yuste, 2011).…”

Section: Pattern Of Pv Immunoreactivity Along the Rostro-caudal Axis mentioning

confidence: 99%

Aging But Not Age-Related Hearing Loss Dominates the Decrease of Parvalbumin Immunoreactivity in the Primary Auditory Cortex of Mice

Rogalla

Hildebrandt

2020

eNeuro

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“…Given that 282 slc39a14 U801-/mutants show evidence of Mn toxicity already at 5 dpf (increased total Mn and 283 reduced locomotor activity), this suggests that bdnf expression is a sensitive read-out for Mn 284 toxicity. Mn associated suppression of BDNF signalling has been linked to diminished 285 numbers of parvalbumin positive cells, mainly GABAergic interneurons (Fairless et al, 2019). 286…”

Section: Mn Toxicity Causes Differential Gene Expression Independent mentioning

confidence: 99%

Loss of slc39a14 causes simultaneous manganese deficiency and hypersensitivity in zebrafish

Tuschl

White

Valdivia

et al. 2020

Preprint

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21 Corresponding authors: 22 k.tuschl@ucl.ac.uk, https://orcid.org/0000-0001-8599-8516 23 emb81@cam.ac.uk, https://orcid.org/0000-0001-6450-744X 24 25 Abbreviated title: slc39a14 deficiency causes Mn dyshomeostasis 26 27 Abstract 30Mutations in SLC39A14, a manganese uptake transporter, lead to a neurodegenerative 31 disorder characterised by accumulation of manganese in the brain and rapidly progressive 32 dystonia-parkinsonism (Hypermanganesemia with Dystonia 2, HMNDYT2). Similar to the 33 human phenotype, zebrafish slc39a14 U801-/mutants show prominent brain manganese 34 accumulation and abnormal locomotor behaviour. In order to identify novel potential targets of 35 manganese neurotoxicity, we performed transcriptome analysis of individual homozygous 36 mutant and sibling slc39a14 U801 zebrafish at five days post fertilisation unexposed and 37 exposed to MnCl2. Anatomical gene enrichment analysis confirmed that differentially 38expressed genes map to the central nervous system and eye. Biological interpretation of 39differentially expressed genes suggests that calcium dyshomeostasis, activation of the 40 unfolded protein response, oxidative stress, mitochondrial dysfunction, lysosomal disruption, 41 apoptosis and autophagy, and interference with proteostasis are key events in manganese 42neurotoxicity. Differential expression of visual phototransduction genes also predicted visual 43 dysfunction in mutant larvae which was confirmed by the absence of visual background 44 adaptation and a diminished optokinetic reflex. Surprisingly, we found a group of differentially 45 expressed genes in mutant larvae that normalised upon MnCl2 treatment suggesting that, in 46 addition to neurotoxicity, manganese deficiency is present either subcellularly or in specific 47 cells or tissues. This may have important implications for treatment as manganese chelation 48 may aggravate neurological symptoms. Our analyses show that slc39a14 U801-/mutant 49 zebrafish present a powerful model to study the cellular and molecular mechanisms underlying 50 disrupted manganese homeostasis. 51 52 Significance statement 53 Manganese neurotoxicity leading to progressive dystonia-parkinsonism is a characteristic 54 feature of Hypermanganesemia with dystonia 2 (HMNDYT2) caused by mutations in 55 SLC39A14, a manganese uptake transporter. Transcriptional profiling in slc39a14 U801 loss-of-56 function zebrafish suggests that, in addition to manganese neurotoxicity, subcellular or cell 57 type specific manganese deficiency contributes to the disease phenotype. Both manganese 58 overload and deficiency appear to be associated with Ca 2+ dyshomeostasis. We further 59 demonstrate that activation of the unfolded protein response, oxidative stress, mitochondrial 60 dysfunction, apoptosis and autophagy, and disrupted proteostasis are likely downstream 61 events in manganese neurotoxicity. Our study shows that the zebrafish slc39a14 U801 loss-of-62 function mutant is a powerful model to elucidate the mechanistic basis of diseases affected by 63 manganese dy...

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Calcium-Binding Proteins as Determinants of Central Nervous System Neuronal Vulnerability to Disease

Cited by 76 publications

References 111 publications

A Multi-Scale Computational Model of Excitotoxic Loss of Dopaminergic Cells in Parkinson’s Disease

A Multi-Scale Computational Model of Excitotoxic Loss of Dopaminergic Cells in Parkinson’s Disease

Aging But Not Age-Related Hearing Loss Dominates the Decrease of Parvalbumin Immunoreactivity in the Primary Auditory Cortex of Mice

Loss of slc39a14 causes simultaneous manganese deficiency and hypersensitivity in zebrafish

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