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Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation
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Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation

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LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis

Tomoya Eguchi1, Tomoki Kuwahara1, Maria Sakurai1

  • 1Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 113-0033 Tokyo, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|September 14, 2018
PubMed

Insights

Leucine-rich repeat kinase 2 (LRRK2) regulates lysosomal response to stress. This study reveals how LRRK2, with Rab GTPases, maintains lysosomal homeostasis, impacting diseases like Parkinson's.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) is implicated in Parkinson's and Crohn's diseases.
  • LRRK2 deficiency causes lysosomal abnormalities in aged animals.
  • The precise mechanisms of LRRK2 in lysosomal regulation are not fully understood.

Purpose of the Study:

  • To elucidate the role of LRRK2 in stress-induced lysosomal response.
  • To identify LRRK2-mediated pathways regulating lysosomal homeostasis.
  • To investigate the function of LRRK2 and its downstream targets in lysosomal stress.

Main Methods:

  • Investigated LRRK2 recruitment and activation on lysosomal membranes under stress.
  • Utilized Rab GTPase screening to identify LRRK2 downstream targets.
  • Examined the effects of LRRK2 and Rab GTPases on lysosomal morphology and secretion.
  • Assessed LRRK2 deficiency effects on lysosomal vacuolation in vivo.

Main Results:

  • Lysosomal overload stress recruits and activates LRRK2 via Rab7L1 (Rab29).
  • LRRK2 phosphorylates Rab8a and Rab10, promoting their accumulation on stressed lysosomes.
  • Rab7L1-LRRK2 pathway attenuates lysosomal enlargement and enhances secretion.
  • Rab8a and Rab10, stabilized by LRRK2, suppress enlargement and promote secretion, respectively.
  • LRRK2 deficiency exacerbates chloroquine-induced lysosomal vacuolation in renal tubules.

Conclusions:

  • A stress-responsive machinery involving Rab7L1, LRRK2, and phosphorylated Rab8/10 maintains lysosomal homeostasis.
  • This pathway is crucial for cellular adaptation to lysosomal overload.
  • Dysregulation of this machinery may contribute to diseases associated with LRRK2.
Keywords:
LRRK2Rab GTPaselysosomephosphorylation

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