Related Experiment Video

Updated: May 23, 2026

Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation
12:49

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

Published on: March 21, 2020

Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein

Michel Fricke1, Anna Mechel1, Lennart Evers1

  • 1University Medical Center Goettingen, Department of Neurology, 37077 Goettingen, Germany.

Cell Reports
|May 21, 2026
PubMed

Insights

Parkinson disease (PD) involves LRRK2 gene mutations affecting RAB GTPases. Disrupting PPM1H impairs axonal transport and alpha-synuclein degradation, linking LRRK2 to PD pathology.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Parkinson disease (PD) is linked to LRRK2 gene mutations that increase kinase activity.
  • LRRK2 regulates intracellular trafficking via RAB GTPases.
  • Axonal transport of autophagosomes is crucial for neuronal health and cargo degradation.

Purpose of the Study:

  • To investigate the role of PPM1H, a LRRK2-counteracting phosphatase, in axonal transport and PD.
  • To elucidate the mechanism linking LRRK2 activity, RAB GTPases, and alpha-synuclein aggregation.

Main Methods:

  • Utilized PPM1H knockout models in neurons.
  • Assessed axonal transport of autophagosomes.
  • Quantified alpha-synuclein (aSyn) degradation and aggregation.
  • Examined the role of LRRK2 kinase activity.

Main Results:

  • PPM1H knockout disrupted axonal autophagosome transport in a gene-dose-dependent manner.
  • Impaired transport led to reduced degradation of axonal alpha-synuclein (aSyn).
  • aSyn aggregation increased in PPM1H knockout neurons, dependent on LRRK2 activity.

Conclusions:

  • Mechanistically links LRRK2-mediated RAB hyperphosphorylation to impaired autophagosomal degradation.
  • Highlights the LRRK2-RAB axis as a critical factor in Parkinson disease pathophysiology.
  • Suggests PPM1H as a potential therapeutic target for PD.
Keywords:
CP: Cell biologyCP: NeuroscienceLRRK2PPM1HRAB GTPasesalpha-synucleinautophagyaxonal transport

More Related Videos

Assaying the Kinase Activity of LRRK2 in vitro06:09

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate11:31

Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate

Published on: September 18, 2013

Related Concept Videos

Parkinson Disease ll: Pathophysiology01:24

Parkinson Disease ll: Pathophysiology

Parkinson disease (PD) is a progressive neurodegenerative disorder primarily affecting movement, with additional non-motor features. Its pathophysiology involves complex interactions among genetic susceptibility, environmental exposures, and cellular dysfunction, including dopaminergic neuron loss, protein aggregation, and mitochondrial impairment.Selective NeurodegenerationA key feature is the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to reduced...
Lysosomal Hydrolases01:22

Lysosomal Hydrolases

Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
Parkinson Disease l: Introduction01:24

Parkinson Disease l: Introduction

Parkinson’s disease is a chronic, progressive neurodegenerative disorder that primarily affects movement. It is characterized by motor symptoms such as resting tremors, muscle rigidity, bradykinesia (slowness of movement), and postural instability. Patients may notice hand tremors at rest, stiffness during movement, or a shuffling gait. In addition to motor features, non-motor symptoms include sleep disturbances, mood and behavioral changes, constipation, and cognitive impairment, all of which...