Pallidin is a novel interacting protein for cytohesin‐2 and regulates the early endosomal pathway and dendritic formation in neurons

Ito, Akiko; Fukaya, Masahiro; Saegusa, Shintaro; Kobayashi, Eizaburo; Sugawara, Takeyuki; Hara, Yoshinobu; Yamauchi, Junji; Okamoto, Hirotsugu; Sakagami, Hiroyuki

doi:10.1111/jnc.14579

Cited by 14 publications

(7 citation statements)

References 101 publications

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“…In addition, reported brainassociated functions of BLOC-1 (A. Ito et al, 2018;Newell-Litwa et al, 2010;Spiegel, Chiu, James, Jentsch, & Karlsgodt, 2015) may underlay a neurologic phenotype of BLOC-1 deficiency. Recognition of these features may facilitate the diagnosis of affected individuals with HPS subtypes associated with BLOC-1 defects.…”

Section: Epidemiology Of Hpsmentioning

confidence: 99%

“…For example, the absence of platelet delta granules is currently essential for the HPS diagnosis, but a subset of subjects with BLOC‐1 may have normal/decreased platelet delta granules and may therefore not be considered for an HPS diagnosis. In addition, reported brain‐associated functions of BLOC‐1 (A. Ito et al, 2018; Newell‐Litwa et al, 2010; Spiegel, Chiu, James, Jentsch, & Karlsgodt, 2015) may underlay a neurologic phenotype of BLOC‐1 deficiency. Recognition of these features may facilitate the diagnosis of affected individuals with HPS subtypes associated with BLOC‐1 defects.…”

Section: Introductionmentioning

confidence: 99%

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Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that~333 Puerto Rican HPS subjects and~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.

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Section: Epidemiology Of Hpsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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“…Besides expression of dominant-negative ARF6, we also demonstrate that the Brefeldin-resistant cytohesin inhibitor secinH3 can partially reverse the decrease in spine density induced by TBC1D24 knockdown. SecinH3 can inhibit ARF6 [18,38] since the ARF6-GEFs ARNO and ARNO2 belong to the cytohesin family and are expressed in hippocampal neuron [81,82]. However, secinH3 does not specifically inhibit ARF6, and the combined effect of not just ARF6 inhibition but also other ARFs might explain why secinH3 treatment alone reduces synapse density while expression of dominant-negative ARF6 does not.…”

Section: Discussionmentioning

confidence: 99%

The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors

Liu¹,

Lyu²,

Kwan³

et al. 2020

PLoS Genet

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Perturbation of synapse development underlies many inherited neurodevelopmental disorders including intellectual disability (ID). Diverse mutations on the human TBC1D24 gene are strongly associated with epilepsy and ID. However, the physiological function of TBC1D24 in the brain is not well understood, and there is a lack of genetic mouse model that mimics TBC1D24 loss-of-function for the study of animal behaviors. Here we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6. Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety. Interestingly, we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution. We further generate the F251L knock-in mice, and the homozygous mutants show increased neuronal excitability, spontaneous seizure and premature death. Moreover, the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory. Our findings therefore uncover a previously uncharacterized postsynaptic function of TBC1D24, and suggest that impaired dendritic spine maintenance contributes to the pathophysiology of individuals harboring TBC1D24 gene mutations. The F251L knock-in mice represent a useful animal model for investigation of the mechanistic link between TBC1D24 loss-of-function and neurodevelopmental disorders.

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“…No. 17404-1-AP, ProteinTech, Rosemont, IL), EFA6D [29], BRAG1 [34], BRAG2 [35], BRAG3 [36], cytohesin-2 [37], Arf6 [38], calbindin (Cat. No.…”

Section: Methodsmentioning

confidence: 99%

Mice lacking EFA6C/Psd2, a guanine nucleotide exchange factor for Arf6, exhibit lower Purkinje cell synaptic density but normal cerebellar motor functions

et al. 2019

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ADP ribosylation factor 6 (Arf6) is a small GTPase that regulates various neuronal events including formation of the axon, dendrites and dendritic spines, and synaptic plasticity through actin cytoskeleton remodeling and endosomal trafficking. EFA6C, also known as Psd2, is a guanine nucleotide exchange factor for Arf6 that is preferentially expressed in the cerebellar cortex of adult mice, particularly in Purkinje cells. However, the roles of EFA6C in cerebellar development and functions remain unknown. In this study, we generated global EFA6C knockout (KO) mice using the CRISPR/Cas9 system and investigated their cerebellar phenotypes by histological and behavioral analyses. Histological analyses revealed that EFA6C KO mice exhibited normal gross anatomy of the cerebellar cortex, in terms of the thickness and cellularity of each layer, morphology of Purkinje cells, and distribution patterns of parallel fibers, climbing fibers, and inhibitory synapses. Electron microscopic observation of the cerebellar molecular layer revealed that the density of asymmetric synapses of Purkinje cells was significantly lower in EFA6C KO mice compared with wild-type control mice. However, behavioral analyses using accelerating rotarod and horizontal optokinetic response tests failed to detect any differences in motor coordination, learning or adaptation between the control and EFA6C KO mice. These results suggest that EFA6C plays ancillary roles in cerebellar development and motor functions.

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Pallidin is a novel interacting protein for cytohesin‐2 and regulates the early endosomal pathway and dendritic formation in neurons

Cited by 14 publications

References 101 publications

Hermansky–Pudlak syndrome: Mutation update

Hermansky–Pudlak syndrome: Mutation update

The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors

Mice lacking EFA6C/Psd2, a guanine nucleotide exchange factor for Arf6, exhibit lower Purkinje cell synaptic density but normal cerebellar motor functions

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