Polyamines, such as spermidine, are essential regulators of brain development, yet how cells control their uptake and extracellular levels remains unclear. Here we show that ATP13A4, a transport protein enriched in glia and prominently expressed in astrocytes, governs brain polyamine balance. Using biochemical, cellular, and animal models, we find that ATP13A4 imports polyamines into cells and thereby limits their availability outside cells. Loss of ATP13A4 simplifies astrocyte morphology and increases the excitatory connections, or synapses, that astrocytes promote between neurons; adding spermidine reproduces these effects, identifying extracellular spermidine as a synapse-promoting signal. In mice lacking Atp13a4, brain polyamines are redistributed, with reduced levels in the cortex and accumulation in cerebrospinal fluid. This is accompanied by excess excitatory synapses, delayed early development, and mild, female-biased behavioral changes in adulthood. Rare ATP13A4 variants linked to neurodevelopmental disorders disrupt its function. Thus, astrocytic polyamine clearance via ATP13A4 tunes extracellular spermidine to shape synapse formation during development. Polyamines help shape brain development, but how brain extracellular levels are controlled has remained unclear. Here, the authors show that astrocytic ATP13A4 clears extracellular spermidine to regulate excitatory synapse formation and neurodevelopment.
S. van Veen, Emily Meeus, D. Irala et al.· Nature Communications· 1 citation
Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl−/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9. Loss- and gain-of-function variants of the endosomal chloride/proton exchanger ClC-3 are associated with neurodevelopmental disorders. Identification and characterization of novel variants expands the clinical spectrum of CLCN3 disease and provides detailed insights into pathogenic mechanisms. Most heterozygous missense variants result in a gain of function when studied in co-expression with TMEM9 β-subunits. Several variants affect ClC-3 residues close to the binding pocket of the TMEM9 carboxy-terminus that directly blocks the chloride pathway, thereby weakening the block. Several other variants, located far from the binding site, affect voltage-dependent gating when studied without TMEM9, thereby enhancing currents at endosomal voltages. These variants also weaken TMEM9-mediated inhibition, revealing a link between gating-associated conformational changes and TMEM9 binding. Most heterozygous missense variants result in a gain of function when studied in co-expression with TMEM9 β-subunits. Several variants affect ClC-3 residues close to the binding pocket of the TMEM9 carboxy-terminus that directly blocks the chloride pathway, thereby weakening the block. Several other variants, located far from the binding site, affect voltage-dependent gating when studied without TMEM9, thereby enhancing currents at endosomal voltages. These variants also weaken TMEM9-mediated inhibition, revealing a link between gating-associated conformational changes and TMEM9 binding. Loss- and gain-of-function variants of the endosomal chloride/proton exchanger ClC-3 are associated with neurodevelopmental disorders. Identification and characterization of novel variants expands the clinical spectrum of CLCN3 disease and provides detailed insights into pathogenic mechanisms.
Maya M. Polovitskaya, T. Tkemaladze, L. Jensen et al.· EMBO Molecular Medicine· 0 citations
These findings define and validate a distinct DNAm episignature for WSKA, providing a valuable diagnostic biomarker to sup - port variant classification and offering insight into the epigenomic consequences of ZNF462 haploinsufficiency.
H. McConkey, Liselot van der Laan, Peter Henneman et al.· 0 citations
Findings further support AP5B1 as a cause of macular dystrophy, identify p.(Leu785Pro) as a relatively frequent pathogenic allele in individuals of European and Ashkenazi Jewish ancestry, and expand the associated phenotypic spectrum to include both isolated macular dystrophy and possible syndromic presentations.
Petra Liskova, L. Dudakova, Karolina Kaminska et al.· HGG advances· 0 citations
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