The sorting receptor Rer1 controls Purkinje cell function via voltage gated sodium channels

Valkova, Christina; Liebmann, Lutz; Krämer, Andreas; Hübner, Christian A.; Kaether, Christoph

doi:10.1038/srep41248

Cited by 13 publications

(25 citation statements)

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“…These findings suggest that Rer1 maintains Notch signaling by supporting proper γ-secretase complex expression to supply a sufficient progenitor pool for cortical development. Recently, it has been reported that Rer1 is also involved in the assembly and transport of voltage-gated sodium channels in Purkinje cell [ 34 ]. Thus, Rer1 could also affect other membrane protein complexes such as voltage-gated sodium channels or the activity of other γ-secretase substrates in addition to Notch1 to regulate brain development and behaviors.…”

Section: Discussionmentioning

confidence: 99%

Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development

et al. 2018

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Rer1 is a retrieval receptor for endoplasmic reticulum (ER) retention of various ER membrane proteins and unassembled or immature components of membrane protein complexes. However, its physiological functions during mammalian development remain unclear. This study aimed to investigate the role of Rer1-mediated quality control system in mammalian development. We show that Rer1 is required for the sufficient cell surface expression and activity of γ-secretase complex, which modulates Notch signaling during mouse cerebral cortex development. When Rer1 was depleted in the mouse cerebral cortex, the number of neural stem cells decreased significantly, and malformation of the cerebral cortex was observed. Rer1 loss reduced γ-secretase activity and downregulated Notch signaling in the developing cerebral cortex. In Rer1-deficient cells, a subpopulation of γ-secretase complexes and components was transported to and degraded in lysosomes, thereby significantly reducing the amount of γ-secretase complex on the cell surface. These results suggest that Rer1 maintains Notch signaling by maintaining sufficient expression of the γ-secretase complex on the cell surface and regulating neural stem cell maintenance during cerebral cortex development.

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Section: Discussionmentioning

confidence: 99%

Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development

et al. 2018

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“…Furthermore, we find that retention in endoplasmic reticulum 1 (Rer1) is the direct target of Ttyh1 action, providing a potential mechanism by which Ttyh1 influences the Notch signaling pathway and thereby brain development. Rer1 has been known to exist in the ER and cis-Golgi and have roles in the regulation of c-secretase activity [17][18][19], intracellular rhodopsin trafficking [20], alpha-synuclein degradation [21], ER retention of peripheral myelin protein 22 (PMP22) [22], and the quality control of some voltage-gated sodium channels [23]. Since Notch has been known to be implicated in tumor progression in the adult, our study should also help better understanding of the molecular basis involved in Ttyh1-implicated phenotypic outcomes in other cellular events such as oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

et al. 2018

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Despite growing evidence linking tweety-homologue 1 (Ttyh1) to normal mammalian brain development and cell proliferation, its exact role has not yet been determined. Here, we show that Ttyh1 is required for the maintenance of neural stem cell (NSC) properties as assessed by neurosphere formation and analyses of cell localization after electroporation. We find that enhanced Ttyh1-dependent stemness of NSCs is caused by enhanced γ-secretase activity resulting in increased levels of Notch intracellular domain (NICD) production and activation of Notch targets. This is a unique function of Ttyh1 among all other Ttyh family members. Molecular analyses revealed that Ttyh1 binds to the regulator of γ-secretase activity Rer1 in the endoplasmic reticulum and thereby destabilizes Rer1 protein levels. This is the key step for Ttyh1-dependent enhancement of γ-secretase activity, as Rer1 overexpression completely abolishes the effects of Ttyh1 on NSC maintenance. Taken together, these findings indicate that Ttyh1 plays an important role during mammalian brain development by positively regulating the Notch signaling pathway through the downregulation of Rer1.

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“…Interestingly, more evidence comes from studies in mice that do not have specific mutations in Na V channels, but in auxiliary subunits like Na V β4 (Ransdell et al, 2017 ) and Fgf14 (Shakkottai et al, 2009 ; Bosch et al, 2015 ), or in the sorting receptor Rer1 ( Rer1 Δ PC ; Valkova et al, 2017 ). Mice with a selective PC deletion of the Na V β4 subunit showed deficits in motor coordination and balance associated with a marked reduction of the Na + resurgent current and spontaneous and evoked firing impairment (Ransdell et al, 2017 ).…”

Section: Ataxia Due To Alterations Of Purkinje Cell Intrinsic Membranmentioning

confidence: 99%

Purkinje Cell Signaling Deficits in Animal Models of Ataxia

Hoxha

Balbo

Miniaci

et al. 2018

Front. Synaptic Neurosci.

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Purkinje cell (PC) dysfunction or degeneration is the most frequent finding in animal models with ataxic symptoms. Mutations affecting intrinsic membrane properties can lead to ataxia by altering the firing rate of PCs or their firing pattern. However, the relationship between specific firing alterations and motor symptoms is not yet clear, and in some cases PC dysfunction precedes the onset of ataxic signs. Moreover, a great variety of ionic and synaptic mechanisms can affect PC signaling, resulting in different features of motor dysfunction. Mutations affecting Na+ channels (NaV1.1, NaV1.6, NaVβ4, Fgf14 or Rer1) reduce the firing rate of PCs, mainly via an impairment of the Na+ resurgent current. Mutations that reduce Kv3 currents limit the firing rate frequency range. Mutations of Kv1 channels act mainly on inhibitory interneurons, generating excessive GABAergic signaling onto PCs, resulting in episodic ataxia. Kv4.3 mutations are responsible for a complex syndrome with several neurologic dysfunctions including ataxia. Mutations of either Cav or BK channels have similar consequences, consisting in a disruption of the firing pattern of PCs, with loss of precision, leading to ataxia. Another category of pathogenic mechanisms of ataxia regards alterations of synaptic signals arriving at the PC. At the parallel fiber (PF)-PC synapse, mutations of glutamate delta-2 (GluD2) or its ligand Crbl1 are responsible for the loss of synaptic contacts, abolishment of long-term depression (LTD) and motor deficits. At the same synapse, a correct function of metabotropic glutamate receptor 1 (mGlu1) receptors is necessary to avoid ataxia. Failure of climbing fiber (CF) maturation and establishment of PC mono-innervation occurs in a great number of mutant mice, including mGlu1 and its transduction pathway, GluD2, semaphorins and their receptors. All these models have in common the alteration of PC output signals, due to a variety of mechanisms affecting incoming synaptic signals or the way they are processed by the repertoire of ionic channels responsible for intrinsic membrane properties. Although the PC is a final common pathway of ataxia, the link between specific firing alterations and neurologic symptoms has not yet been systematically studied and the alterations of the cerebellar contribution to motor signals are still unknown.

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The sorting receptor Rer1 controls Purkinje cell function via voltage gated sodium channels

Cited by 13 publications

References 50 publications

Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development

Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

Purkinje Cell Signaling Deficits in Animal Models of Ataxia

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