Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Berridge, Michael J.

doi:10.4161/pri.21767

Cited by 181 publications

(133 citation statements)

References 86 publications

(103 reference statements)

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“…Many factors in aging neurons, such as increased release of Ca 2+ from intracellular stores and increased Ca 2+ influx through L-type voltage-gated calcium channels, lead to sustained elevation of free Ca 2+ concentration (56,58). Moreover, calcium dysregulation has been implicated in the development of major neural disorders such as Alzheimer's disease, BD, and schizophrenia, and drugs that reduce Ca 2+ signaling activity have in some cases proved successful in alleviating symptoms (59,60). Interestingly, NCS-1 is highly upregulated in schizophrenic and BD patients, and substantial evidence suggests that resting and activated levels of Ca 2+ are elevated in BD (61).…”

Section: Discussionmentioning

confidence: 99%

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

Heidarsson

Naqvi

Otazo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurodegenerative disorders are strongly linked to protein misfolding, and crucial to their explication is a detailed understanding of the underlying structural rearrangements and pathways that govern the formation of misfolded states. Here we use singlemolecule optical tweezers to monitor misfolding reactions of the human neuronal calcium sensor-1, a multispecific EF-hand protein involved in neurotransmitter release and linked to severe neurological diseases. We directly observed two misfolding trajectories leading to distinct kinetically trapped misfolded conformations. Both trajectories originate from an on-pathway intermediate state and compete with native folding in a calcium-dependent manner. The relative probability of the different trajectories could be affected by modulating the relaxation rate of applied force, demonstrating an unprecedented real-time control over the free-energy landscape of a protein. Constant-force experiments in combination with hidden Markov analysis revealed the free-energy landscape of the misfolding transitions under both physiological and pathological calcium concentrations. Remarkably for a calcium sensor, we found that higher calcium concentrations increased the lifetimes of the misfolded conformations, slowing productive folding to the native state. We propose a rugged, multidimensional energy landscape for neuronal calcium sensor-1 and speculate on a direct link between protein misfolding and calcium dysregulation that could play a role in neurodegeneration.protein folding | NCS-1 | off-pathway intermediate | conformational dynamics | optical trapping

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Section: Discussionmentioning

confidence: 99%

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

Heidarsson

Naqvi

Otazo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…A decrease in the expression of PV is associated with epileptic seizure susceptibility (Marco et al, 1997;Schwaller et al, 2004), mild behavioral and motor alterations (Farré-Castany et al, 2007), schizophrenia (Pinault, 2011;Lewis et al, 2012), bipolar disorder (Berridge, 2013) and autism spectrum disorder (Oblak et al, 2011). In particular, a reduction in the density of parvalbumin-positive neurons, and schizophrenic traits have recently been demonstrated in the methyl azoxymethanol acetate model of schizophrenia (Lodge et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Visual thalamocortical circuits in parvalbumin-deficient mice

Lintas¹,

Schwaller²,

Villa³

2013

Brain Research

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“…The 2-APB analogues presented in this study could be proven to be excellent lead compounds for many human diseases including heart disorders [59], Alzheimer`s [60,61] and Huntington`s disease [62,63].…”

Section: We Listed the Chemical Structures Of The Best 9 Compoundsmentioning

confidence: 97%

2-Aminoethyl diphenylborinate (2-APB) analogues: part 2. regulators of Ca2+ release and consequent cellular processes

Ozaki¹

2014

Arch Physiol

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In order to obtain compounds with modified 2-APB activities, we synthesized number of bis-boron 2-APB analogues and analyzed their inhibitory activities for SOCE and IICR. Adducts of amino acids with bis-borinic acid showed the highest activity. The IC 50 of 2-APB for SOCE inhibition was 3 µM, while the IC 50 of 2051 bis(4,4'(phenyllysineboryl)benzyl) ether was 0.2 µM. By using these compounds, we may be able to regulate Ca 2+ release and consequent cellular processes more efficiently than with 2-APB.

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Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Cited by 181 publications

References 86 publications

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

Visual thalamocortical circuits in parvalbumin-deficient mice

2-Aminoethyl diphenylborinate (2-APB) analogues: part 2. regulators of Ca2+ release and consequent cellular processes

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