Increased Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel in Adult-Onset Neuronal Ceroid Lipofuscinosis

Donnelier, Julien; Braun, Samuel T.; Dolzhanskaya, Natalia; Ahrendt, Eva; Braun, Andrew P.; Velinov, Milen; Braun, Janice E. A.

doi:10.1371/journal.pone.0125205

Cited by 18 publications

(29 citation statements)

References 42 publications

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“…This finding is consistent with the idea that CSPα suppresses BK α trafficking to the presynaptic terminals, and likely enhances neurotransmitter release (see Section 3.1.3). Synaptosomal BK α protein abundance was also significantly elevated in the postmortem cortex of an ANCL patient (Donnelier et al, 2015), but it remains to be determined whether BK channel upregulation actually contributes to the etiology of ANCL.…”

Section: Role Of Bk Channels In Cns Function and Pathologiesmentioning

confidence: 99%

BK Channels in the Central Nervous System

Contet

Goulding

Kuljis

et al. 2016

International Review of Neurobiology

143

170

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Large conductance Ca2+- and voltage-activated K+ (BK) channels are widely distributed in the postnatal central nervous system (CNS). BK channels play a pleiotropic role in regulating the activity of brain and spinal cord neural circuits by providing a negative feedback mechanism for local increases in intracellular Ca2+ concentrations. In neurons, they regulate the timing and duration of K+ influx such that they can either increase or decrease firing depending on the cellular context, and they can suppress neurotransmitter release from presynaptic terminals. In addition, BK channels located in astrocytes and arterial myocytes modulate cerebral blood flow. Not surprisingly, both loss and gain of BK channel function have been associated with CNS disorders such as epilepsy, ataxia, mental retardation, and chronic pain. On the other hand, the neuroprotective role played by BK channels in a number of pathological situations could potentially be leveraged to correct neurological dysfunction.

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Section: Role Of Bk Channels In Cns Function and Pathologiesmentioning

confidence: 99%

BK Channels in the Central Nervous System

Contet

Goulding

Kuljis

et al. 2016

International Review of Neurobiology

143

170

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“…This disorder is caused by a mutation (deletion of leucine 116) of the cysteine string protein α, a synaptic vesicle protein and molecular chaperone essential for neuroprotection (Donnelier et al . ), known to regulate large conductance BK channels at the cell surface (Kyle et al . ).…”

Section: Structural Properties Of Bk Channel Complexes and Localizatimentioning

confidence: 99%

“…A dysregulation of BK channels has been observed also in synaptosomes obtained from postmortem cortical specimens of an individual affected by an adult form J Physiol 594.13 of adult neuronal ceroid lipofuscinosis (ANCL). This disorder is caused by a mutation (deletion of leucine 116) of the cysteine string protein α, a synaptic vesicle protein and molecular chaperone essential for neuroprotection (Donnelier et al 2015), known to regulate large conductance BK channels at the cell surface (Kyle et al 2013). ANCL is characterized by uncoordinated movements, shaking, temperature-sensitive paralysis and reduced lifespan.…”

Section: Bk Channels Dysfunction In Neurological Disordersmentioning

confidence: 99%

“…ANCL is characterized by uncoordinated movements, shaking, temperature-sensitive paralysis and reduced lifespan. Although the underlying mechanisms are still unclear, the increased expression of presynaptic BK channels in individuals with mutated cysteine string protein α may contribute to the pathogenic cascade of events underlying ANCL (Kyle et al 2013;Ahrendt et al 2014;Donnelier et al 2015).…”

Section: Bk Channels Dysfunction In Neurological Disordersmentioning

confidence: 99%

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Presynaptic BK channels control transmitter release: physiological relevance and potential therapeutic implications

Griguoli

Sgritta

Cherubini

2016

The Journal of Physiology

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BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary β and γ subunits to regulate Ca 2+ sensitivity, voltage dependence and gating properties. Abundantly expressed in the CNS, they have the peculiar characteristic of being activated by both voltage and intracellular calcium rise. The increase in intracellular calcium via voltage-dependent calcium channels (Ca v ) during spiking triggers conformational changes and BK channel opening. This narrows the action potential and Marilena Griguoli received her PhD degree at the International School for Advanced Studies in Trieste. After a Post-doc at the Interdisciplinary Institute for Neuroscience in Bordeaux in the lab of C. Mulle, she joined EBRI as a senior scientist. Her research is focused on cholinergic regulation of the hippocampal circuits in vivo using electrophysiology combined with opto/chemogenetic tools. Martina Sgritta received her PhD in Biomedical Science at the University of Pavia. She then moved as a Post-doc to EBRI in Rome, where she is studying with electrophysiological tools synaptic plasticity in an animal model of autism. Enrico Cherubini trained as a child neurologist and is full professor of physiology at the International School for Advanced Studies in Trieste. Recently he moved to EBRI in Rome as a scientific director. His research interest focuses on the molecular and cellular mechanisms regulating synaptic plasticity processes particularly during postnatal development. induces a fast after-hyperpolarization that shuts calcium channels. The tight coupling between BK and Ca v channels at presynaptic active zones makes them particularly suitable for regulating calcium entry and neurotransmitter release. While in most synapses, BK channels exert a negative control on transmitter release under basal conditions, in others they do so only under pathological conditions, serving as an emergency brake to protect against hyperactivity. In particular cases, by interacting with other channels (i.e. limiting the activation of the delayed rectifier and the inactivation of Na + channels), BK channels induce spike shortening, increase in firing rate and transmitter release. Changes in transmitter release following BK channel dysfunction have been implicated in several neurological disorders including epilepsy, schizophrenia, fragile X syndrome, mental retardation and autism. In particular, two mutations, one in the α and one in the β3 subunit, resulting in a gain of function have been associated with epilepsy. Hence, these discoveries have allowed identification of BK channels as new drug targets for therapeutic intervention. Abstract figure legend BK channels control transmitter release. A, BK channels tightly coupled with Ca v contribute to the repolarizing phase of the action potential, spike width and transmitter release. B, loss of BK channels induced by genetic deletion causes, as in the presence of selective blockers, action potential broadening and increase in t...

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“…Mutant and wild type CSPα interact to form high molecular weight aggregates 7, 22, 25 . However, the link between aggregates, AFSM and lysosomes is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis

Benitez

Sands

2017

Sci Rep

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Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities. AFSM accumulation correlates with CSPα aggregation and both are susceptible to pharmacological modulation of ALP function. In addition, we demonstrate that endogenous CSPα is present in the lysosome-enriched fractions and co-localizes with lysosome markers in soma, neurites and synaptic boutons. Overexpression of CSPα wild-type (WT) decreases lysotracker signal, secreted lysosomal enzymes and SNAP23-mediated lysosome exocytosis. CSPα WT, mutant and aggregated CSPα are degraded mainly by the ALP but this disease-causing mutation exhibits a faster rate of degradation. Co-expression of both WT and mutant CSPα cause a block in the fusion of autophagosomes/lysosomes. Our data suggest that aggregation‐dependent perturbation of ALP function is a relevant pathogenic mechanism for AD-ANCL and supports the use of AFSM or CSPα aggregation as biomarkers for drug screening purposes.

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Increased Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel in Adult-Onset Neuronal Ceroid Lipofuscinosis

Cited by 18 publications

References 42 publications

BK Channels in the Central Nervous System

BK Channels in the Central Nervous System

Presynaptic BK channels control transmitter release: physiological relevance and potential therapeutic implications

Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis

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