Abstract
Huntington's disease manifests due to abnormal CAG trinucleotide expansion, in the first exon of the Huntingtin gene and disease progression involves genetic, immune, and environmental components. The pathogenesis is characterized by the formation of Inclusion Bodies, disruption of neuronal circuitry, cellular machinery, and apoptosis, resulting in gradual and progressive loss of neuronal cells, ultimately leading to nervous system dysfunction. Thus, the present study was conducted to assess the effect of two Ayurvedic formulations, Guduchi and Madhuyashti, on Huntington's phenotype, using Drosophila as a model system. The Huntington phenotype was ectopically induced in the Drosophila eye using the UAS-GAL4 binary system and the effect of the two Ayurvedic formulations were assessed by feeding the progenies on them. Degeneration was observed microscopically and Real Time-PCR was done to assay the alterations in the different transcripts of the innate immune pathways and JNK signaling pathway. Immunostaining was performed to assay different gene expression patterns. The present study shows that Guduchi and Madhuyashti, endowed with immunomodulatory and intellect promoting properties, aggravates polyQ mediated neurodegeneration. We provide evidence that these formulations enhance JNK signaling by activating the MAP 3 K, dTAK1, which regulates the expression of Drosophila homologue for JNK. Sustained, rather than a transient expression of JNK leads to excessive production of Anti-Microbial Peptides without involving the canonical transcription factors of the Toll or IMD pathways, NF-κB. Enhanced JNK expression also increases caspase levels, with a concomitant reduction in cell proliferation, which may further contribute to increased degeneration. This is a report linking the functional relevance of Guduchi and Madhuyashti with molecular pathways, which can be important for understanding their use in therapeutic applications and holds promise for mechanistic insight into the mammalian counterpart.
