Purine Nucleotides Metabolism and Signaling in Huntington’s Disease: Search for a Target for Novel Therapies

Huntington’s disease (HD) is a multi-system disorder that is caused by expanded CAG repeats within the exon-1 of the huntingtin (HTT) gene that translate to the polyglutamine stretch in the HTT protein. HTT interacts with the proteins involved in gene transcription, endocytosis, and metabolism. HTT may also directly or indirectly affect purine metabolism and signaling. We aimed to review existing data and discuss the modulation of the purinergic system as a new therapeutic target in HD. Impaired intracellular nucleotide metabolism in the HD affected system (CNS, skeletal muscle and heart) may lead to extracellular accumulation of purine metabolites, its unusual catabolism, and modulation of purinergic signaling. The mechanisms of observed changes might be different in affected systems. Based on collected findings, compounds leading to purine and ATP pool reconstruction as well as purinergic receptor activity modulators, i.e., P2X7 receptor antagonists, may be applied for HD treatment.