Insights into Caspase-6 Mutations and Neuropathology in Huntington's Disease and Psychiatric Disorders: A Structural Genomics and Drug Repurposing Approach.

Huntington's disease (HD) is an inherited neurodegenerative condition that typically appears later in life, marked by progressive motor impairments, cognitive deterioration, and a range of psychiatric disturbances. Crucial to HD pathogenesis is the aberrant activation of caspase-6 (CASP6), which leads to the cleavage of mutant huntingtin (mHTT) protein, generating a toxic N-terminal fragment. CASP6 activity is elevated in human HD brains and is associated with the progression of neuropathology. This study aims to investigate the impact of deleterious mutations in CASP6 on the catalytic activity and stability of the protein. Identification of such mutations may be implicated in developing improved diagnostic approaches. Out of 225 single-point amino acid substitutions screened, 13 were found to be pathogenic and tend to form CASP6 aggregates. Among them, one mutation, F55V, was found in the highly conserved region, which may affect CASP6 function. We further employed a drug repurposing approach to identify potential CASP6 inhibitors for therapeutic development against HD. The integrated virtual screening and MD simulations analysis has suggested two repurposed drugs, Risperidone and Lorpiprazole, against CASP6. These results highlighted that targeting of CASP6 is a promising strategy for therapeutic management of HD and offers a starting point for designing novel interventions. As psychiatric symptoms in HD share neuropathological mechanisms with major psychiatric disorders, targeting CASP6 may provide insights into therapeutic strategies for both. These findings highlight CASP6 as a promising target for HD therapy and broader research in neuropsychiatric disorders. While this study is limited to computational modelling, it offers a valuable starting point for downstream experimental research.