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The endoplasmic reticulum contributes to lysosomal tubulation/sorting driven by LRRK2
Luis Bonet-Ponce1, Mark R Cookson1
1Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
Molecular Biology of the Cell
|August 31, 2022
Summary
Damaged lysosomes form tubules and vesicles through a process called LYTL, driven by the Parkinson
Area of Science:
- Cell Biology
- Organelle Dynamics
- Neurodegenerative Diseases
Background:
- Lysosomes are crucial organelles involved in cellular waste disposal and signaling.
- Lysosomal membrane damage triggers adaptive remodeling responses.
- The Parkinson's disease protein LRRK2 plays a role in lysosomal function.
Purpose of the Study:
- To characterize the novel process of Lysosomal Tubulation/sorting driven by LRRK2 (LYTL) after membrane damage.
- To investigate the role of the endoplasmic reticulum (ER) in LYTL.
- To explore the relevance of LYTL to Parkinson's disease pathology.
Main Methods:
- Spinning-disk microscopy combined with superresolution imaging.
- Induction of lysosomal membrane damage using LLOMe.
- Manipulation of endoplasmic reticulum morphology.
Main Results:
- Damaged lysosomes form tubules that are sorted into vesicles (LYTL).
- LRRK2 recruits JIP4 to lysosomes, promoting tubulation via phosphorylated RAB proteins.
- Tubular endoplasmic reticulum (ER) colocalizes with lysosomal tubule fission sites and is necessary for LYTL.
Conclusions:
- Contact with tubular ER is essential for lysosomal membrane sorting during LYTL.
- The discovered LYTL process involves LRRK2 and ER-lysosome interactions.
- These findings offer insights into Parkinson's disease mechanisms involving LRRK2 and lysosomal dysfunction.
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