TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons

Aprile, Davide; Fruscione, Floriana; Baldassari, Sımona; Fadda, Manuela; Ferrante, Daniele; Falace, Antonio; Buhler, Emmanuelle; Sartorelli, Jacopo; Represa, Alfonso; Baldelli, Pietro; Benfenati, Fabio; Zara, Federico

doi:10.1038/s41418-019-0313-x

Cited by 28 publications

(35 citation statements)

References 44 publications

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“…It should be noted that expression of dominant-negative ARF6 partially but not fully reverses the reduction of spine number induced by TBC1D24-shRNA. This agrees with a very recent study showing that dominantnegative ARF6 only partially rescues the impaired axonal growth after TBC1D24 knockdown in young neuron [35]. It is therefore likely that TBC1D24 mediates its action in neuron partly through suppression of ARF6 activity, but there are other parallel signaling pathways involved.…”

Section: Discussionsupporting

confidence: 92%

“…In Drosophila, TBC1D24 regulates neurotransmitter release through modulation of Rab35 [16]. However, over-expression of TBC1D24 suppresses ARF6 activity in Hela cells [13], and ARF6 is implicated as the downstream target of TBC1D24 in mammalian neuron [17,35]. We found that the mammalian TBC1D24 interacts with ARF6 but not Rab35 (Fig 3A).…”

Section: Tbc1d24 Regulates Dendritic Spine Maintenance Through the Sumentioning

confidence: 82%

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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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Section: Discussionsupporting

confidence: 92%

Section: Tbc1d24 Regulates Dendritic Spine Maintenance Through the Sumentioning

confidence: 82%

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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“…This is not surprising as vesicular trafficking orchestrated by RAB proteins and their interaction partners in general is essential at neuronal synaptic terminals for neurotransmitter uptake, recycling, and release (Binotti, Jahn, & Chua, 2016). For example, loss of the disease‐related protein TBC1D24 in rat primary cortical neurons causes impairment in membrane trafficking at the growth cone that induces an axon specification defect (Aprile et al, 2019). Similarly, TBC1D24 deficiency in Neuro2a cells leads to impaired endocytosis and shorter neurites (Finelli et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

et al. 2020

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The family of Tre2‐Bub2‐Cdc16 (TBC)‐domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP‐independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss‐of‐function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B‐deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.

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“…TBC1D24 is a pleiotropic gene and variations cause both ARHL (DFNB86; MIM 614617), ADHL (DFNA65; MIM 616044), and several epilepsy syndromes such as AR DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome (MIM 220500), AR early infantile epileptic encephalopathy-16 (MIM 615338) and AR familial infantile myoclonic epilepsy (MIM 605021; Mucha et al, 2017 ). To date, pathomechanistic investigations on TBC1D24 variations have been hampered by a lack of genotype-phenotype correlation when analyzing homozygous and compound heterozygous AR variants (Bakhchane et al, 2015 ; Aprile et al, 2019 ). Missense variations in the TBC domain and a truncating frameshift variation in the TLDc domain are known to cause prelingual-onset ARHL (Rehman et al, 2014 ; Bakhchane et al, 2015 ; Danial-Farran et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation

Parzefall

Frohne

Koenighofer

et al. 2020

Front. Cell. Neurosci.

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Background : Hereditary hearing loss is a disorder with high genetic and allelic heterogeneity. Diagnostic screening of candidate genes commonly yields novel variants of unknown clinical significance. TBC1D24 is a pleiotropic gene associated with recessive DOORS syndrome, epileptic encephalopathy, myoclonic epilepsy, and both recessive and dominant hearing impairment. Genotype-phenotype correlations have not been established to date but could facilitate diagnostic variant assessment and elucidation of pathomechanisms. Methods and Results : Whole-exome and gene panel screening identified a novel (c.919A>C; p.Asn307His) causative variant in TBC1D24 in two unrelated Caucasian families with Autosomal dominant (AD) nonsyndromic late-onset hearing loss. Protein modeling on the Drosophila TBC1D24 ortholog Skywalker crystal structure showed close interhelix proximity (6.8Å) between the highly conserved residue p.Asn307 in α18 and the position of the single known pathogenic dominant variation (p.Ser178Leu) in α11 that causes a form of deafness with similar clinical characteristics. Conclusion : Genetic variants affecting two polar hydrophilic residues in neighboring helices of TBC1D24 cause AD nonsyndromic late-onset hearing loss. The spatial proximity of the affected residues suggests the first genotype-phenotype association in TBC1D24 -related disorders. Three conserved residues in α18 contribute to the formation of a functionally relevant cationic phosphoinositide binding pocket that regulates synaptic vesicle trafficking which may be involved in the molecular mechanism of disease.

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TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons

Cited by 28 publications

References 44 publications

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

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

Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation

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