ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity

Abstract

ATP9A, a lipid flippase of the class II P4-ATPases, is involved in cellular vesicle trafficking. Its homozygous variants are linked to neurodevelopmental disorders in humans. However, its physiological function, the underlying mechanism as well as its pathophysiological relevance in humans and animals are still largely unknown. Here, we report two independent families in which the nonsense mutations c.433C>T/c.658C>T/c.983G>A (p. Arg145*/p. Arg220*/p. Trp328*) in ATP9A (NM_006045.3) cause autosomal recessive hypotonia, intellectual disability (ID) and attention deficit hyperactivity disorder (ADHD). Atp9a null mice show decreased muscle strength, memory deficits and hyperkinetic movement disorder, recapitulating the symptoms observed in patients. Abnormal neurite morphology and impaired synaptic transmission are found in the primary motor cortex and hippocampus of the Atp9a null mice. ATP9A is also required for maintaining neuronal neurite morphology and the viability of neural cells in vitro. It mainly localizes to endosomes and plays a pivotal role in endosomal recycling pathway by modulating small GTPase RAB5 and RAB11 activation. However, ATP9A pathogenic mutants have aberrant subcellular localization and cause abnormal endosomal recycling. These findings provide strong evidence that ATP9A deficiency leads to neurodevelopmental disorders and synaptic dysfunctions in both humans and mice, and establishes novel regulatory roles for ATP9A in RAB5 and RAB11 activity-dependent endosomal recycling pathway and neurological diseases.

Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology

“…DOPEY2 is located on human chromosome 21 and has been investigated for its possible contribution to Down Syndrome 59 , whereas DOPEY1 loss of function in rats causes defective myelin formation 60 . Loss of function in the TAT-5 ortholog ATP9A results in aberrant neurite morphology and endosomal recycling defects in mice 61 , and ATP9A variants have been linked to human neurodevelopmental disorders 62,63 . Our findings taken together with results from other model organisms suggest that a DIP2/FRY/DOPEY/Flippase pathway could be involved in maintenance of neuronal morphology in humans, and that altered activity of this pathway may contribute to neurological disorders.…”

Circ4207 regulates vasculogenic mimicry formation in colorectal cancer through the miR-20b-5p/VEGFA axis

“…Circ4207 is a 238 nt circular transcript spliced from exons 10 and 11 of the ATP9A (ATPase phospholipid transporting 9A, NM_006044.3) gene on chromosome 20. ATP9A is a phospholipid-ipping enzyme of class II P4-ATPase, which is involved in vesicular transport [31,32] and neuronal development [33]. The splice site was con rmed by Sanger sequencing, and divergent primer was used to con rm the loop characteristics.…”

Expanding the Genetic and Mutation Spectrum of ASPM-associated Neurodevelopmental Disorders

“…In the recent past, investigation of primary microcephaly and NDDs from a genetic, psychological, neuroanatomical, and molecular perspective discovered unique genes and identified related pathways. Molecular genetics and developmental cognitive neuroscience are now being integrated, which is a result of enormous breakthroughs in all fields of study (Deng et al, 2023;Meng et al, 2023;Umair, 2023). Our understanding of developmental brain disorders will be improved by discovering population-wide variations and novel related genes (Asiri et al, 2020;Khan et al, 2020;Nøstvik et al, 2021;Umair et al, 2021).…”