Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, U.S.A.
Denali Therapeutics, San Francisco, CA 94080, U.S.A.
Biochem Soc Trans. 2024 Aug 28;52(4):1909-1919. doi: 10.1042/BST20240087.
Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including membrane damage. Lysosomal dysfunction plays a central role in the pathobiology of Parkinson's disease (PD). Gain-of-function mutations in Leucine-rich repeat kinase 2 (LRRK2) cause familial PD and genetic variations in its locus increase the risk of developing the sporadic form of the disease. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by LRRK2), wherein membrane-damaged lysosomes generate tubules sorted into mobile vesicles. Subsequently, these vesicles interact with healthy lysosomes. LYTL is orchestrated by LRRK2 kinase activity, via the recruitment and phosphorylation of a subset of RAB GTPases. Here, we summarize the current understanding of LYTL and its regulation, as well as the unknown aspects of this process.
溶酶体是动态的细胞结构，能够自适应地重塑其膜以响应刺激，包括膜损伤。溶酶体功能障碍在帕金森病（PD）的病理生物学中起核心作用。富含亮氨酸重复激酶 2（LRRK2）的功能获得性突变导致家族性 PD，其基因座的遗传变异增加了散发型疾病的发病风险。我们之前发现了一个我们称之为 LYTL（由 LRRK2 驱动的溶酶体小管化/分拣）的过程，其中膜损伤的溶酶体产生管状结构，被分拣到可移动的囊泡中。随后，这些囊泡与健康的溶酶体相互作用。LYTL 由 LRRK2 激酶活性通过募集和磷酸化一组 RAB GTPases 来协调。在这里，我们总结了对 LYTL 及其调节的当前理解，以及该过程的未知方面。
