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Published on: October 6, 2015
Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice
Elisabetta Bonfanti1, Tiziana Bonifacino2, Stefano Raffaele1
1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1G93A ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1G93A mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management.
Insights
In amyotrophic lateral sclerosis (ALS), increased GPR17 receptor impairs oligodendrocyte precursor cell (OPC) repair. Targeting GPR17 with montelukast shows promise for restoring OPC function and potentially treating ALS.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Medicine
Background:
- Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration linked to oligodendrocyte dysfunction.
- Oligodendrocyte precursor cells (OPCs) are crucial for myelin repair, but their capacity is impaired in ALS.
- The P2Y-like G protein-coupled receptor 17 (GPR17) regulates OPC maturation and is implicated in other neurodegenerative diseases.
Purpose of the Study:
- To investigate the role of GPR17 in the SOD1G93A mouse model of ALS.
- To determine if GPR17 can be pharmacologically targeted to correct oligodendrocyte alterations in ALS.
Main Methods:
- Western-blot and immunohistochemical analyses were used to assess GPR17 protein levels in spinal cords of ALS mice.
- OPCs were isolated from SOD1G93A mice and treated with the GPR17 antagonist montelukast in vitro.
- Cellular differentiation assays were performed to evaluate OPC reparative capacity.
Main Results:
- GPR17 protein levels were significantly elevated in the spinal cord of SOD1G93A mice at both pre-symptomatic and late symptomatic stages.
- Mature oligodendrocytes degenerated and were not adequately replaced in ALS mice.
- OPCs from ALS mice showed impaired differentiation, which was rescued by montelukast treatment.
Conclusions:
- GPR17 is upregulated in an ALS mouse model, correlating with oligodendrocyte dysfunction and myelin defects.
- Pharmacological antagonism of GPR17 with montelukast can restore the differentiation capacity of ALS-derived OPCs.
- Targeting GPR17 represents a potential therapeutic strategy for counteracting motor neuron loss in ALS.
