Altered Voltage Dependent Calcium Currents in a Neuronal Cell Line Derived From the Cerebral Cortex of a Trisomy 16 Fetal Mouse, an Animal Model of Down Syndrome

Acuña, Mario A.; Pérez-Núñez, Ramón; Noriega, Jorge; Cárdenas, Ana Marı́a; Bacigalupo, Juan; Delgado, Ricardo; Arriagada, Christian; Segura‐Aguilar, Juan; Caviedes, Raúl; Caviedes, Pablo

doi:10.1007/s12640-011-9304-5

Cited by 5 publications

(1 citation statement)

References 38 publications

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“…The CTb cell line, derived from the brain cortex of trisomy 16 (Ts16) mice, an animal model of DS, overexpresses most of the genes of the DS critical region (Reeves et al, 1986 ), including Rcan1 (Lange et al, 2004 ). Similar to primary culture of central neurons from Ts16 mouse fetus, CTb cells display altered Ca 2+ currents and cytosolic Ca 2+ signals (Cárdenas et al, 1999 ; Rojas et al, 2008 ; Acuña et al, 2012 ). Cholinergic function is also impaired, which is characterized by a reduced fractional acetylcholine release (Fiedler et al, 1994 ; Allen et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

RCAN1 Knockdown Reverts Defects in the Number of Calcium-Induced Exocytotic Events in a Cellular Model of Down Syndrome

Vásquez-Navarrete

Martı́nez

Ory

et al. 2018

Front. Cell. Neurosci.

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In humans, Down Syndrome (DS) is a condition caused by partial or full trisomy of chromosome 21. Genes present in the DS critical region can result in excess gene dosage, which at least partially can account for DS phenotype. Although regulator of calcineurin 1 (RCAN1) belongs to this region and its ectopic overexpression in neurons impairs transmitter release, synaptic plasticity, learning and memory, the relative contribution of RCAN1 in a context of DS has yet to be clarified. In the present work, we utilized an in vitro model of DS, the CTb neuronal cell line derived from the brain cortex of a trisomy 16 (Ts16) fetal mouse, which reportedly exhibits acetylcholine release impairments compared to CNh cells (a neuronal cell line established from a normal littermate). We analyzed single exocytotic events by using total internal reflection fluorescence microscopy (TIRFM) and the vesicular acetylcholine transporter fused to the pH-sensitive green fluorescent protein (VAChT-pHluorin) as a reporter. Our analyses showed that, compared with control CNh cells, the trisomic CTb cells overexpress RCAN1, and they display a reduced number of Ca2+-induced exocytotic events. Remarkably, RCAN1 knockdown increases the extent of exocytosis at levels comparable to those of CNh cells. These results support a critical contribution of RCAN1 to the exocytosis process in the trisomic condition.

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Section: Introductionmentioning

confidence: 99%

RCAN1 Knockdown Reverts Defects in the Number of Calcium-Induced Exocytotic Events in a Cellular Model of Down Syndrome

Vásquez-Navarrete

Martı́nez

Ory

et al. 2018

Front. Cell. Neurosci.

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Overexpressed Down Syndrome Cell Adhesion Molecule (DSCAM) Deregulates P21-Activated Kinase (PAK) Activity in an In Vitro Neuronal Model of Down Syndrome: Consequences on Cell Process Formation and Extension

et al. 2016

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In humans, Down syndrome (DS) is caused by the presence of an extra copy of autosome 21. The most striking finding in DS patients is intellectual disability and the onset of Alzheimer's disease (AD)-like neuropathology in adulthood. Gene overdose is most likely to underlie both developmental impairments, as well as altered neuronal function in DS. Lately, the disruption of cellular signaling and regulatory pathways has been implicated in DS pathophysiology, and many of such pathways may represent common targets for diverse DS-related genes, which could in turn represent attractive therapeutical targets. In this regard, one DS-related gene Down Syndrome Cell Adhesion Molecule (DSCAM), has important functions in neuronal proliferation, maturation, and synaptogenesis. p21-associated kinases (PAKs) appear as a most interesting possibility for study, as DSCAM is known to regulate the PAKs pathway. Hence, in DS, overexpressed DSCAM could deregulate PAKs activity and affect signaling pathways that regulate synaptic plasticity such as dendritic spine dynamics and axon guidance and growth. In the present work, we used an immortalized cell line derived from the cerebral cortex of an animal model of DS such as the trisomy 16 (Ts16) fetal mouse (named CTb), and a similar cell line established from a normal littermate (named CNh), to study the effect of DSCAM in the PAKs pathway. The present study shows that DSCAM is overexpressed in CTb cells by approximately twofold, compared to CNh cells. Congruently, PAK1, as well as its downstream effectors LIMK and cofilin, stay phosphorylated for longer periods after DSCAM activation in the CTb cells, leading to an altered actin dynamics, expressed as an increased basal F/G ratio and reduced neurite growth, in the trisomic condition. The present work presents the correlation between DSCAM gene overexpression and a dysregulation of the PAK pathway, resulting in altered morphological parameters of neuronal plasticity in the trisomic cell line, namely decreased number and length of processes.

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Parkinson’s Disease: The Mitochondria-Iron Link

Muñoz

Carrasco

Campos

et al. 2016

Parkinson's Disease

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Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson's disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences—mitochondrial dysfunction, iron accumulation, and oxidative damage—generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson's disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation—by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways—is a viable therapy for retarding this cycle.

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Altered Voltage Dependent Calcium Currents in a Neuronal Cell Line Derived From the Cerebral Cortex of a Trisomy 16 Fetal Mouse, an Animal Model of Down Syndrome

Cited by 5 publications

References 38 publications

RCAN1 Knockdown Reverts Defects in the Number of Calcium-Induced Exocytotic Events in a Cellular Model of Down Syndrome

RCAN1 Knockdown Reverts Defects in the Number of Calcium-Induced Exocytotic Events in a Cellular Model of Down Syndrome

Overexpressed Down Syndrome Cell Adhesion Molecule (DSCAM) Deregulates P21-Activated Kinase (PAK) Activity in an In Vitro Neuronal Model of Down Syndrome: Consequences on Cell Process Formation and Extension

Parkinson’s Disease: The Mitochondria-Iron Link

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