Gastrodia elata alleviates mutant huntingtin aggregation through mitochondrial function and biogenesis mediation

According to the Compendium of Materia Medica, Gastrodia elata (GE) Blume is a top-grade herbal medicine frequently used to treat dizziness, headaches, tetanus, and epilepsy, suggesting that it affects neurological functions. Although studies have supported its effects in preventing diverse neurodegenerations such as Huntington's disease (HD), its mechanisms require further investigation.

To investigate the ability of the molecular mechanism of GE to prevent mutant huntingtin (mHTT) protein aggregation by focusing on mitochondrial function and biogenesis, which have been proposed as the therapeutic targets of HD.

mHtt overexpression in pheochromocytoma (PC12) cells was used as an in vitro cell model of HD. A retardation assay was applied to measure protein aggregation during Htt expression. Cotransfection with transcriptional genes was used to test their relationships with HTT aggregates by monitoring with a confocal laser scanning microscope. Western blot analysis was used to estimate protein expression under different drug treatments or when cotransfected with other related genes.

Mutant, abnormal Htt overexpression resulted in significant protein aggregation in PC12 cells. GE dose-dependently attenuated mHTT aggregates and increased cyclic-AMP response element-binding protein (CREB) phosphorylation. Adenosine A_2A-R receptor (A_2A-R) antagonist counteracted these phenomena. CREB overexpression significantly attenuated mHTT aggregation. GE increased the promoter activity and expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Furthermore, wild-type PGC-1α but not mutant PGC-1α overexpression attenuated mHTT aggregates.

GE attenuated mHtt aggregation by mediating mitochondrial function and biogenesis through the A_2A-R/PKA/CREB/PGC-1α-dependent pathway.