LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size.
Jenny Serra-VinardellMaxwell B SandlerRaffaella De PaceJavier Manzella-LapeiraAntony C CougnouxKeyvan KeyvanfarWendy J IntroneJoseph A BrzostowskiMichael Emmerson WardWilliam A GahlPrashant SharmaMay Christine C MalicdanPublished in: Cellular and molecular life sciences : CMLS (2023)
Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients' induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype.
Keyphrases
- induced pluripotent stem cells
- fluorescent probe
- living cells
- cell death
- endothelial cells
- spinal cord
- cell cycle arrest
- induced apoptosis
- signaling pathway
- oxidative stress
- endoplasmic reticulum stress
- end stage renal disease
- newly diagnosed
- intellectual disability
- gene expression
- transcription factor
- genome wide
- single molecule
- cerebral ischemia
- wild type
- replacement therapy
- smoking cessation