Benzothiazole-Based LRRK2 Inhibitors as Wnt Enhancers and Promoters of Oligodendrocytic Fate
Josefa Zaldivar-Diez1, Lingling Li2, Ana M Garcia1
1Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Abstract:
Leucine rich repeat kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson's disease (PD). However, despite the significant amount of research done in the past decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/β-catenin signaling pathway. Furthermore, compounds 5 and 14 were able to promote neural progenitors proliferation and drive their differentiation toward neuronal and oligodendrocytic cell fates. These results suggest potential new avenues for the application of LRRK2 inhibitors in demyelinating diseases in which oligodendrocyte cell-death is one of the pathological features.
Insights
Novel benzothiazole inhibitors targeting Leucine rich repeat kinase 2 (LRRK2) promote neural progenitor proliferation and differentiation. This suggests LRRK2 inhibitors may treat demyelinating diseases by protecting oligodendrocytes.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Leucine rich repeat kinase 2 (LRRK2) is implicated in Parkinson's disease (PD), but its precise function remains unclear.
- The therapeutic application of LRRK2 inhibitors is nascent, with early-stage clinical trials commencing.
- Understanding LRRK2's role in neurogenesis and gliogenesis is crucial for developing new treatments.
Purpose of the Study:
- To investigate the molecular mechanism of LRRK2 in controlling neurogenesis and gliogenesis.
- To design and synthesize novel benzothiazole-based LRRK2 inhibitors.
- To evaluate the therapeutic potential of these inhibitors in neural cell differentiation.
Main Methods:
- Synthesis of novel benzothiazole-based compounds targeting LRRK2.
- Assessment of LRRK2 inhibitor effects on the Wnt/β-catenin signaling pathway.
- Analysis of compounds' impact on neural progenitor cell proliferation and differentiation.
Main Results:
- The synthesized benzothiazole derivatives effectively modulated the Wnt/β-catenin signaling pathway.
- Compounds 5 and 14 significantly promoted neural progenitor proliferation.
- These compounds directed differentiation towards neuronal and oligodendrocytic cell fates.
Conclusions:
- LRRK2 inhibitors, specifically benzothiazole derivatives, can influence neural cell fate.
- Compounds 5 and 14 demonstrate potential for promoting neuronal and oligodendrocyte differentiation.
- These findings suggest a novel therapeutic application for LRRK2 inhibitors in demyelinating diseases characterized by oligodendrocyte loss.
Related Concept Videos
02:54Canonical Wnt Signaling Pathway
01:41Non-Canonical Wnt Signaling Pathways
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
01:20Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...