Abstract:
Background and purpose: The therapeutic potential of cannabinoids in Huntington's disease (HD) has been investigated by several groups with complex and sometimes contrasting results. We sought to examine key points of intersection between cannabinoid receptor 1 (CB_{1}) signalling, survival and the formation of mutant huntingtin aggregates in HD. Experimental approach: Using a simplified pheochromocytoma (PC12) cell model of HD expressing exon 1 of wild-type or mutant huntingtin, we assayed cell death and aggregate formation using high-throughput cytotoxicity and image-based assays respectively. Key results: CB_{1} activation by HU210 conferred a small but significant level of protection against mutant huntingtin-induced cell death. Pertussis toxin uncoupled HU210 from the inhibition of cAMP, preventing rescue of cell death. Phosphorylation of extracellular signal-regulated kinase (ERK) was also critical to CB_{1}-mediated rescue. Conversely, treatments that elevated cAMP exacerbated mutant huntingtin-induced cell death. Despite opposing effects on HD cell survival, both HU210 and compounds that elevated cAMP increased the formation of mutant huntingtin aggregates. The increase in aggregation by HU210 was insensitive to Pertussis toxin and UO126, suggesting a G-protein alpha subtype s (G_{s})-linked mechanism. Conclusions and implications: We suggest that the CB_{1} receptor, through G-protein alpha subtype i/o (G_{i/o})-linked, ERK-dependent signal transduction, is a therapeutic target in HD. However the protective potential of CB_{1} may be limited by promiscuous coupling to G_{s}, the stimulation of cAMP formation and increased aggregate formation. This may underpin the poor therapeutic efficacy of cannabinoids in more complex model systems and suggest that therapies that are selective for the G_{i/o}, ERK pathway may be of most benefit in HD.
