A Trimeric Protein Complex Functions as a Synaptic Chaperone Machine

Tobaben, Sönke; Thakur, Pratima; Fernández‐Chacón, Rafael; Südhof, Thomas C.; Rettig, Jens; Stahl, Bernd

doi:10.1016/s0896-6273(01)00427-5

Cited by 201 publications

(227 citation statements)

References 50 publications

(8 reference statements)

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“…In particular, a cochaperone complex composed of hsc70 and CSP (cysteine string protein) is present in the presynaptic neurotransmitter vesicles (Tobaben et al, 2001). This complex, together with hsp90, has been proposed to control neurotransmitter release (Sakisaka et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Gerges¹,

Tran²,

Backos³

et al. 2004

J. Neurosci.

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The delivery of neurotransmitter receptors into synapses is essential for synaptic function and plasticity. In particular, AMPA-type glutamate receptors (AMPA receptors) reach excitatory synapses according to two distinct routes: a regulated pathway, which operates transiently during synaptic plasticity, and a constitutive pathway, which maintains synaptic function under conditions of basal transmission. However, the specific mechanisms that distinguish these two trafficking pathways are essentially unknown. Here, we evaluate the role of the molecular chaperone hsp90 (heat shock protein 90) in excitatory synaptic transmission in the hippocampus. On one hand, we found that hsp90 is necessary for the efficient neurotransmitter release at the presynaptic terminal. In addition, we identified hsp90 as a critical component of the cellular machinery that delivers AMPA receptors into the postsynaptic membrane. Using the hsp90-specific inhibitors radicicol and geldanamycin, we show that hsp90 is required for the constitutive trafficking of AMPA receptors into synapses during their continuous cycling between synaptic and nonsynaptic sites. In contrast, hsp90 function is not required for either the surface delivery of AMPA receptors into the nonsynaptic plasma membrane or for the acute, regulated delivery of AMPA receptors into synapses during plasticity induction (long-term potentiation). The synaptic cycling of AMPA receptors was also blocked by an hsp90-binding tetratricopeptide repeat (TPR) domain, suggesting that the role of hsp90 in AMPA receptor trafficking is mediated by a TPR domaincontaining protein. These results demonstrate new roles for hsp90 in synaptic function by controlling neurotransmitter release and, independently, by mediating the continuous cycling of synaptic AMPA receptors.

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Section: Discussionmentioning

confidence: 99%

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Gerges¹,

Tran²,

Backos³

et al. 2004

J. Neurosci.

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“…Synaptic activity increases the rate of both glycolysis and respiration (44), presumably to provide energy for multiple ATPdependent steps in transmitter synthesis, vesicle preparation, and recycling (45)(46)(47). Bcl-x L may increase the availability of ATP by increasing the permeability of the mitochondrial outer membrane or other mechanism (15,16).…”

Section: Bcl-xl May Regulate Availability Of Atp For Synaptic Transmimentioning

confidence: 99%

Bcl-x _L induces Drp1-dependent synapse formation in cultured hippocampal neurons

Li¹,

Chen

Jones³

et al. 2008

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

213

233

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Maturation of neuronal synapses is thought to involve mitochondria. Bcl-xL protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-xL is abundant. Here, we report that overexpression of Bcl-xL postsynaptically increases frequency and amplitude of spontaneous miniature synaptic currents in rat hippocampal neurons in culture. Bcl-xL, overexpressed either pre or postsynaptically, increases synapse number, the number and size of synaptic vesicle clusters, and mitochondrial localization to vesicle clusters and synapses, likely accounting for the changes in miniature synaptic currents. Conversely, knockdown of Bcl-xL or inhibiting it with ABT-737 decreases these morphological parameters. The mitochondrial fission protein, dynamin-related protein 1 (Drp1), is a GTPase known to localize to synapses and affect synaptic function and structure. The effects of Bcl-xL appear mediated through Drp1 because overexpression of Drp1 increases synaptic markers, and overexpression of the dominant-negative dnDrp1-K38A decreases them. Furthermore, Bcl-xL coimmunoprecipitates with Drp1 in tissue lysates, and in a recombinant system, Bcl-xL protein stimulates GTPase activity of Drp1. These findings suggest that Bcl-xL positively regulates Drp1 to alter mitochondrial function in a manner that stimulates synapse formation.Bcl-2 ͉ synaptic transmission ͉ mitochondria ͉ cell death ͉ ABT-737

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“…Such continuous membrane traffic requires specific mechanisms to deal with the use-dependent aging and denaturation of proteins. One such mechanism may involve the synaptic vesicle protein cysteine string protein (CSP) ␣ that is thought to function as a cochaperone in presynaptic terminals (2,3).…”

mentioning

confidence: 99%

“…5 and 6). CSP␣ activates the ATPase activity of Hsc70 (7,8) and forms a trimeric complex with Hsc70 and the tetratricopeptide repeat protein SGT (3). This complex catalyzes the ATP-dependent refolding of denatured luciferase (3).…”

mentioning

confidence: 99%

“…CSP␣ activates the ATPase activity of Hsc70 (7,8) and forms a trimeric complex with Hsc70 and the tetratricopeptide repeat protein SGT (3). This complex catalyzes the ATP-dependent refolding of denatured luciferase (3). Invertebrates have a single CSP gene, whereas mammals express three CSP genes: CSP␣ that is widely distributed but highly enriched in brain, and CSP␤ and CSP␥ that are primarily found in testis (2).…”

mentioning

confidence: 99%

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CSPα-deficiency causes massive and rapid photoreceptor degeneration

Schmitz

Tabares²,

Khimich³

et al. 2006

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

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Cysteine string protein (CSP) ␣ is an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40-type cochaperones. Previous studies showed that deletion of CSP␣ in mice leads to massive lethal neurodegeneration but did not clarify how the neurodegeneration affects specific subpopulations of neurons. Here, we analyzed the effects of the CSP␣ deficiency on tonically active ribbon synapses of the retina and the inner ear. We show that CSP␣-deficient photoreceptor terminals undergo dramatic and rapidly progressive neurodegeneration that starts before eye opening and initially does not affect other retinal synapses. These changes are associated with progressive blindness. In contrast, ribbon synapses of auditory hair cells did not exhibit presynaptic impairments in CSP␣-deficient mice. Hair cells, but not photoreceptor cells or central neurons, express CSP␤, thereby accounting for the lack of a hair-cell phenotype in CSP␣ knockout mice. Our data demonstrate that tonically active ribbon synapses in retina are particularly sensitive to the deletion of CSP␣ and that expression of at least one CSP isoform is essential to protect such tonically active synapses from neurodegeneration.hair cell ͉ ribbon synapse ͉ electroretinogram ͉ chaperone ͉ blindness S ynaptic vesicle exo-and endocytosis is mediated by a sophisticated machinery that allows nerve terminals to operate at high speed (1). Such continuous membrane traffic requires specific mechanisms to deal with the use-dependent aging and denaturation of proteins. One such mechanism may involve the synaptic vesicle protein cysteine string protein (CSP) ␣ that is thought to function as a cochaperone in presynaptic terminals (2, 3).CSP␣ is an abundant presynaptic protein (4) that contains a string of cysteine residues and a DNA-J domain that functionally collaborates with the DNA-K domains of Hsc70 proteins (reviewed in refs. 5 and 6). CSP␣ activates the ATPase activity of Hsc70 (7,8) and forms a trimeric complex with Hsc70 and the tetratricopeptide repeat protein SGT (3). This complex catalyzes the ATP-dependent refolding of denatured luciferase (3). Invertebrates have a single CSP gene, whereas mammals express three CSP genes: CSP␣ that is widely distributed but highly enriched in brain, and CSP␤ and CSP␥ that are primarily found in testis (2).Analyses of knockout (KO) mice revealed that CSP␣-deficient mice are relatively normal at birth but exhibit a progressive lethal phenotype that results in death after 2-4 months (2). Recordings in the Calyx of Held synapse of CSP␣ KO mice documented that CSP␣ is not required for N-, P͞Q-, and R-type Ca 2ϩ -channel function or Ca 2ϩ -triggered vesicle exocytosis. Instead, in the absence of CSP␣, the calyx synapse developed an age-dependent functional impairment, consistent with a role for CSP␣ as part of a molecular chaperone that makes it possible for synapses to keep running for extended time periods (2). Although this hypothesis was in agreement with previous observations in CSP-deficient flies (4), alt...

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A Trimeric Protein Complex Functions as a Synaptic Chaperone Machine

Cited by 201 publications

References 50 publications

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Bcl-x _L induces Drp1-dependent synapse formation in cultured hippocampal neurons

CSPα-deficiency causes massive and rapid photoreceptor degeneration

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A Trimeric Protein Complex Functions as a Synaptic Chaperone Machine

Cited by 201 publications

References 50 publications

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Bcl-x L induces Drp1-dependent synapse formation in cultured hippocampal neurons

CSPα-deficiency causes massive and rapid photoreceptor degeneration

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Product

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Bcl-x _L induces Drp1-dependent synapse formation in cultured hippocampal neurons