Bracey, Kai et al. (2015) International Worm Meeting "Elucidating the role of the novel transcription factor FKH-8 in regulating dopaminergic signaling levels.."

Nelms, Brian, Bracey, Kai

[

International Worm Meeting,

2015]

FKH-8 is a member of the fork head transcription factor family, which plays wide and important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Research in our lab has identified a role for FKH-8 in regulating C. elegans dopaminergic (DA) neuron function, which is vital for coordination of movement and learning behaviors. The 8 DA neurons of the hermaphrodite worm share a high degree of conservation in key biosynthetic and signaling components with human DA neurons. Mutant worms that are devoid of the fkh-8 gene display a swimming-induced paralysis (SWIP) phenotype that suggests extrasynaptic dopamine is inhibiting the cholinergic motor neuron circuits through the DOP-3 receptor, as occurs with loss of the dopamine transporter gene, dat-1. To test if fkh-8 mutants also display the SWIP phenotype through this mechanism, we tested fkh-8;dop-3 double mutants for rescue of the SWIP phenotype. We found that without dop-3, the fkh-8 mutants do not have the SWIP phenotype, suggesting that the SWIP phenotype displayed in fkh-8 mutants is dependent on the DOP-3 receptor.Extrasynaptic dopamine could result if FKH-8 normally dampens the synthesis of dopamine, such that fkh-8 mutants have increased production of dopamine, resulting in the SWIP phenotype. I am also generating a double mutant fkh-8;bas-1 strain (bas-1 encodes the enzyme aromatic amino acid decarboxylase that converts L-dopa to dopamine), among others, to evaluate the dependence of the fkh-8 SWIP phenotype on levels of dopamine synthesis. Our study aims to identify a role of FKH-8 in the dopamine pathway and allow investigation of gene targets.

Xiao L et al. (2020) Rejuvenation Res "The Traditional Formula Kai-Xin-San Alleviates Polyglutamine-Mediated Neurotoxicity by Modulating Proteostasis Network in Caenorhabditis elegans."

Tian J, Huang Z, Xiao L, Zhou L, Yang F, Wang Q, Zhang J, Jin N, Li H

[

Rejuvenation Res,

2020]

The inherited polyglutamine (polyQ) expansion diseases are characterized by progressive accumulation of aggregation-prone polyQ proteins, which may provoke proteostasis imbalance and result in significant neurotoxicity. Using polyQ transgenic Caenorhabditis elegans models, we find that Kai-Xin-San (KXS), a well-known herbal formula traditionally used to treat mental disorders in China, can alleviate polyQ-mediated neuronal death and associated chemosensory deficiency. Intriguingly, KXS does not reduce polyQ aggregation in vitro as demonstrated by Thioflavin-T test, but does inhibit polyQ aggregation in C. elegans models, indicating an indirect aggregation-inhibitory mechanism. Further investigation reveals that KXS can modulate two key arms of the protein quality control system, that is, heat shock response and autophagy, to clear polyQ aggregates, but has little effect on proteasome activity. In addition, KXS is able to reduce oxidative stress, which is involved in proteostasis and neurodegeneration, but has no effect on life span or dietary restriction response. To examine potential interaction of the four component herbs of KXS, a dissection strategy was used to study the effects of differential herbal combinations in C. elegans polyQ models. While the four herbs do contribute additively to KXS function, Panax ginseng is found to be the most effective constituent. Taken together, these findings not only demonstrate the neuroprotective ability of KXS but also suggest its potential as a proteostasis regulator in protein aggregation disorders and provide an insight into the mechanism studies of traditionally used complex prescriptions and their rationality.