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Lysosomal swelling triggers LRRK2 activity.

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Lysosomal swelling, not membrane damage, activates Leucine-Rich Repeat Kinase 2 (LRRK2). This discovery reveals LRRK2 as a sensor of lysosomal volume and mechanical stress, crucial for understanding LRRK2-linked diseases.

Keywords:
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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The precise triggers for Leucine-Rich Repeat Kinase 2 (LRRK2) activation in physiological conditions remain unclear.
  • LRRK2 is known to play a role in lysosomal functions, but the upstream signals are not fully understood.

Purpose of the Study:

  • To identify the physiological cues that activate endogenous Leucine-Rich Repeat Kinase 2 (LRRK2).
  • To investigate the relationship between lysosomal swelling and LRRK2 activity.

Main Methods:

  • Induction of lysosomal swelling via PIKfyve inhibition and indigestible osmolyte uptake.
  • Measurement of LRRK2-mediated Rab phosphorylation.
  • Pharmacological rescue of lysosomal ionic imbalances.

Main Results:

  • Lysosomal swelling, independent of membrane damage, selectively triggers LRRK2-mediated Rab phosphorylation.
  • PIKfyve inhibition induces Rab phosphorylation accumulation, which is suppressed by rescuing lysosomal swelling.
  • Mechanical stress from swelling increases LRRK2 activity in both swollen and non-swollen lysosomes.

Conclusions:

  • Leucine-Rich Repeat Kinase 2 (LRRK2) functions as a sensor of lysosomal volume and mechanical stress.
  • LRRK2 is part of an endolysosomal surveillance system responding to lysosomal distension.
  • These findings reframe the role of LRRK2 in the context of lysosomal volume regulation and mechanical sensing.