Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
11025553 | Neurobiology of Disease | 2019 | 58 Pages |
Abstract
Loss-of-function mutations in the recycling endosomal (Na+,K+)/H+ exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p.Gly218Arg; G218R) of a conserved residue in its ion translocation domain that results in a potential gain-of-function. The patient manifested several core symptoms typical of CS, including pronounced cognitive impairment, mutism, epilepsy, ataxia and microcephaly; however, deterioration of motor function often observed after the first decade of life in CS children with total loss of SLC9A6/NHE6 function was not evident. In transfected non-neuronal cells, complex glycosylation and half-life of the G218R were significantly decreased compared to the wild-type transporter. This correlated with elevated ubiquitination and partial proteasomal-mediated proteolysis of G218R. However, a major fraction was delivered to the plasma membrane and endocytic pathways. Compared to wild-type, G218R-containing endosomes were atypically alkaline and showed impaired uptake of recycling endosomal cargo. Moreover, instead of accumulating in recycling endosomes, G218R was redirected to multivesicular bodies/late endosomes and ejected extracellularly in exosomes rather than progressing to lysosomes for degradation. Attenuated acidification and trafficking of G218R-containing endosomes were also observed in transfected hippocampal neurons, and correlated with diminished dendritic branching and density of mature mushroom-shaped spines and increased appearance of filopodia-like protrusions. Collectively, these findings expand our understanding of the genetic diversity of CS and further elucidate a critical role for SLC9A6/NHE6 in fine-tuning recycling endosomal pH and cargo trafficking, processes crucial for the maintenance of neuronal polarity and mature synaptic structures.
Keywords
XLIDAP-1AMPARhsp70TrkBCANXADP-ribosylation factor 6PHVARF6MVBGAPDHTGNARNOGFPOMIMERADTCLLAMP1TransferrinESCRTTFRDMSOα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptorX-linked intellectual disabilitySDS-PAGESodium dodecyl sulfate polyacrylamide gel electrophoresismultivesicular bodiesendoplasmic reticulum-associated degradationtropomyosin receptor kinase BNeurodegenerationExtracellular vesiclesCNSDimethylsulfoxidecentral nervous systemTrans-Golgi networkendoplasmic reticulumPlasma membraneMembrane traffickingendosomal sorting complex required for transportwild-typepolymerase chain reactionPCROnline Mendelian Inheritance in Manlate endosomesheat shock protein 70lysosome-associated membrane protein 1green fluorescent proteincalnexinglyceraldehyde-3-phosphate dehydrogenasetransferrin receptorUbiquitin
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Authors
Alina Ilie, Andy Y.L. Gao, Annie Boucher, Jaeok Park, Albert M. Berghuis, Mariëtte J.V. Hoffer, Yvonne Hilhorst-Hofstee, R. Anne McKinney, John Orlowski,