SNARE proteins rescue impaired autophagic flux in Down syndrome


Autoři: Stefanos Aivazidis aff001;  Abhilasha Jain aff001;  Abhishek K. Rauniyar aff001;  Colin C. Anderson aff001;  John O. Marentette aff001;  David J. Orlicky aff002;  Kristofer S. Fritz aff001;  Peter S. Harris aff001;  David Siegel aff001;  Kenneth N. Maclean aff003;  James R. Roede aff001
Působiště autorů: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, United States of America aff001;  Department of Pathology, University of Colorado School of Medicine, Aurora, CO, United States of America aff002;  Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States of America aff003;  The Linda Crnic Institute for Down Syndrome, University of Colorado, Aurora, CO, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223254

Souhrn

Down syndrome (DS) is a chromosomal disorder caused by trisomy of chromosome 21 (Ts21). Unbalanced karyotypes can lead to dysfunction of the proteostasis network (PN) and disrupted proteostasis is mechanistically associated with multiple DS comorbidities. Autophagy is a critical component of the PN that has not previously been investigated in DS. Based on our previous observations of PN disruption in DS, we investigated possible dysfunction of the autophagic machinery in human DS fibroblasts and other DS cell models. Following induction of autophagy by serum starvation, DS fibroblasts displayed impaired autophagic flux indicated by autophagolysosome accumulation and elevated p62, NBR1, and LC3-II abundance, compared to age- and sex-matched, euploid (CTL) fibroblasts. While lysosomal physiology was unaffected in both groups after serum starvation, we observed decreased basal abundance of the Soluble N-ethylmaleimide-sensitive-factor Attachment protein Receptor (SNARE) family members syntaxin 17 (STX17) and Vesicle Associated Membrane Protein 8 (VAMP8) indicating that decreased autophagic flux in DS is due at least in part to a possible impairment of autophagosome-lysosome fusion. This conclusion was further supported by the observation that over-expression of either STX17 or VAMP8 in DS fibroblasts restored autophagic degradation and reversed p62 accumulation. Collectively, our results indicate that impaired autophagic clearance is a characteristic of DS cells that can be reversed by enhancement of SNARE protein expression and provides further evidence that PN disruption represents a candidate mechanism for multiple aspects of pathogenesis in DS and a possible future target for therapeutic intervention.

Klíčová slova:

Autophagic cell death – Cultured fibroblasts – Fibroblasts – Immunofluorescence – Induced pluripotent stem cells – Lysosomes – SNARE proteins – Down syndrome


Zdroje

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