SNX14 mutations affect endoplasmic reticulumassociated neutral lipid metabolism in autosomal recessive spinocerebellar ataxia 20

Dale Bryant, Yang Liu, Sanchari Datta, Hanaa Hariri, Marian Seda, Glenn Anderson, Emma Peskett, Charalambos Demetriou, Sergio Sousa, Dagan Jenkins, Peter Clayton, Maria Bitner-Glindzicz, Gudrun E. Moore, W. Mike Henne, Philip Stanier

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Mutations in SNX14 cause the autosomal recessive cerebellar ataxia 20 (SCAR20). Mutations generally result in loss of protein although several coding region deletions have also been reported. Patient-derived fibroblasts show disrupted autophagy, but the precise function of SNX14 is unknown. The yeast homolog, Mdm1, functions in endoplasmic reticulum (ER)-lysosome/ vacuole inter-organelle tethering, but functional conservation in mammals is still required. Here, we show that loss of SNX14 alters but does not block autophagic flux. In addition, we find that SNX14 is an ER-associated protein that functions in neutral lipid homeostasis and inter-organelle crosstalk. SNX14 requires its N-terminal transmembrane helices for ER localization, while the Phox homology (PX) domain is dispensable for subcellular localization. Both SNX14-mutant fibroblasts and SNX14KO HEK293 cells accumulate aberrant cytoplasmic vacuoles, suggesting defects in endolysosomal homeostasis. However, ER-late endosome/lysosome contact sites are maintained in SNX14KO cells, indicating that it is not a prerequisite for ER-endolysosomal tethering. Further investigation of SNX14- deficiency indicates general defects in neutral lipid metabolism. SNX14KO cells display distinct perinuclear accumulation of filipin in LAMP1-positive lysosomal structures indicating cholesterol accumulation. Consistent with this, SNX14KO cells display a slight but detectable decrease in cholesterol ester levels, which is exacerbated with U18666A. Finally, SNX14 associates with ER-derived lipid droplets (LD) following oleate treatment, indicating a role in ER-LD crosstalk. We therefore identify an important role for SNX14 in neutral lipid homeostasis between the ER, lysosomes and LDs that may provide an early intervention target to alleviate the clinical symptoms of SCAR20.

Original languageEnglish (US)
Pages (from-to)1927-1940
Number of pages14
JournalHuman molecular genetics
Issue number11
StatePublished - Jun 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'SNX14 mutations affect endoplasmic reticulumassociated neutral lipid metabolism in autosomal recessive spinocerebellar ataxia 20'. Together they form a unique fingerprint.

Cite this