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LRRK2: an éminence grise of Wnt-mediated neurogenesis?
Daniel C Berwick1, Kirsten Harvey
1Department of Pharmacology, University College London School of Pharmacy, University College London London, UK.
Abstract:
The importance of leucine-rich repeat kinase 2 (LRRK2) to mature neurons is well-established, since mutations in PARK8, the gene encoding LRRK2, are the most common known cause of Parkinson's disease. Nonetheless, despite the LRRK2 knockout mouse having no overt neurodevelopmental defect, numerous lines of in vitro data point toward a central role for this protein in neurogenesis. Roles for LRRK2 have been described in many key processes, including neurite outgrowth and the regulation of microtubule dynamics. Moreover, LRRK2 has been implicated in cell cycle control, suggesting additional roles in neurogenesis that precede terminal differentiation. However, we contend that the suggested function of LRRK2 as a scaffolding protein at the heart of numerous Wnt signaling cascades provides the most tantalizing link to neurogenesis in the developing brain. Numerous lines of evidence show a critical requirement for multiple Wnt pathways in the development of certain brain regions, not least the dopaminergic neurons of the ventral mid-brain. In conclusion, these observations indicate a function of LRRK2 as a subtle yet critical mediator of the action of Wnt ligands on developing neurons. We suggest that LRRK2 loss- or gain-of-function are likely modifiers of developmental phenotypes seen in animal models of Wnt signaling deregulation, a hypothesis that can be tested by cross-breeding relevant genetically modified experimental strains.
Insights
Leucine-rich repeat kinase 2 (LRRK2) plays a subtle yet critical role in brain development and neurogenesis, particularly in dopaminergic neurons. Its function as a scaffolding protein in Wnt signaling pathways is key to these developmental processes.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of Parkinson's disease.
- While LRRK2 knockout mice show no developmental defects, in vitro studies suggest a role in neurogenesis.
- LRRK2 is involved in neurite outgrowth, microtubule dynamics, and cell cycle control.
Purpose of the Study:
- To investigate the role of LRRK2 in neurogenesis, particularly in the developing brain.
- To explore the potential function of LRRK2 as a scaffolding protein in Wnt signaling pathways.
- To link LRRK2's function to the development of dopaminergic neurons.
Main Methods:
- Literature review and synthesis of existing in vitro and in vivo data.
- Analysis of LRRK2's proposed role as a scaffolding protein in Wnt signaling.
- Hypothesizing LRRK2's function in the context of neurodevelopmental processes.
Main Results:
- LRRK2 is implicated in key neurogenesis processes, including neurite outgrowth and cell cycle control.
- LRRK2's function as a scaffolding protein in Wnt signaling pathways is a critical link to neurogenesis.
- Wnt signaling pathways are essential for the development of specific brain regions, including dopaminergic neurons.
Conclusions:
- LRRK2 acts as a subtle but critical mediator of Wnt ligand actions on developing neurons.
- LRRK2's loss or gain of function may modify developmental phenotypes in Wnt signaling deregulation models.
- This hypothesis can be tested through cross-breeding genetically modified animal strains.
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