Related Experiment Video

Updated: Mar 10, 2026

Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate
11:31

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

Published on: September 18, 2013

10.5K

Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor α-mediated neurotoxicity

Dong Hwan Ho1, Wongi Seol1, Jin Hwan Eun2

  • 1InAm Neuroscience Research Center, Sanbon Medical Center, Collage of Medicine, Wonkwang University, 321 Sanbon-ro, Gunposhi, Gyeonggido, Republic of Korea.

Biochemical and Biophysical Research Communications
|December 5, 2016
PubMed

Insights

Leucine-rich repeat kinase (LRRK2) activity in microglia drives Parkinson's disease neuroinflammation. LRRK2 phosphorylates p53, increasing TNFα and dopaminergic neuron death.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Immunology

Background:

  • Leucine-rich repeat kinase (LRRK2) is a key gene in Parkinson's disease (PD).
  • The G2019S mutation increases LRRK2 kinase activity.
  • LRRK2 phosphorylates p53 in neurons; its inhibition reduces neuroinflammation in microglia.

Purpose of the Study:

  • To investigate LRRK2's role in microglia-mediated neuroinflammation in Parkinson's disease.
  • To determine if LRRK2 phosphorylates p53 in microglia.
  • To assess the impact of LRRK2-mediated p53 phosphorylation on pro-inflammatory cytokine secretion and neuronal survival.

Main Methods:

  • Utilized BV2 microglia cell line and primary microglia from G2019S transgenic mice.
  • Transfected BV2 cells with wild-type and phosphomimetic p53 (T304/377D).
  • Treated cells with lipopolysaccharide (LPS) and assessed TNFα secretion, conditioned media neurotoxicity, and rescue with etanercept.

Main Results:

  • LRRK2 phosphorylates p53 in BV2 microglia.
  • Phosphomimetic p53 (T304/377D) significantly increased LPS-induced TNFα secretion.
  • Conditioned media from transfected cells induced dopaminergic neuron death, which was rescued by etanercept.
  • Primary microglia from G2019S mice showed increased TNFα secretion upon LPS treatment.

Conclusions:

  • LRRK2 kinase activity in microglia contributes to Parkinson's disease neuroinflammation.
  • Phosphorylation of p53 at T304/T377 by LRRK2 is a mechanism driving this neuroinflammation.
  • Targeting LRRK2 or TNFα may offer therapeutic strategies for Parkinson's disease.
Keywords:
LRRK2NeuroinflammationParkinson's diseasep53

More Related Videos

Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag08:55

Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag

Published on: December 14, 2017

16.2K
Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

9.2K

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.4K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.1K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.7K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
9.0K
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
9.9K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.0K