• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), but the underlying pathophysiological mechanisms and the normal function of this large multidomain protein remain speculative. To address the role of this protein in vivo, we generated three different LRRK2 mutant mouse lines. Mice completely lacking the LRRK2 protein (knock-out, KO) showed an early-onset (age 6 weeks) marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells. Mice expressing a LRRK2 kinase-dead (KD) mutant from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung. KD mutants had dramatically reduced full-length LRRK2 protein levels in the kidney and this genetic effect was mimicked pharmacologically in wild-type mice treated with a LRRK2-selective kinase inhibitor. Knock-in (KI) mice expressing the G2019S PD-associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice. The autophagy marker LC3 remained unchanged but kidney mTOR and TCS2 protein levels decreased in KD and increased in KO and KI mice. Unexpectedly, KO and KI mice suffered from diastolic hypertension opposed to normal blood pressure in KD mice. Our findings demonstrate a role for LRRK2 in kidney and lung physiology and further show that LRRK2 kinase function affects LRRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity. These novel aspects of peripheral LRRK2 biology critically impact ongoing attempts to develop LRRK2 selective kinase inhibitors as therapeutics for PD.

Pubmed ID: 21828077

Authors

  • Herzig MC
  • Kolly C
  • Persohn E
  • Theil D
  • Schweizer T
  • Hafner T
  • Stemmelen C
  • Troxler TJ
  • Schmid P
  • Danner S
  • Schnell CR
  • Mueller M
  • Kinzel B
  • Grevot A
  • Bolognani F
  • Stirn M
  • Kuhn RR
  • Kaupmann K
  • van der Putten PH
  • Rovelli G
  • Shimshek DR

Journal

Human molecular genetics

Publication Data

November 1, 2011

Associated Grants

None

Mesh Terms

  • Animals
  • Blood Pressure
  • Dopamine
  • Dopamine Agonists
  • Dopamine Antagonists
  • Enzyme Stability
  • Homeostasis
  • Kidney
  • Kidney Tubules, Proximal
  • Lung
  • Lysosomes
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Mutant Strains
  • Motor Activity
  • Pneumocytes
  • Protein-Serine-Threonine Kinases
  • Signal Transduction