Abstract
Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson’s disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases.
Highlights
Aggregation-prone proteins, e.g. α -synuclein (α -syn), amyloid-β, Tau and polyglutamine-containing proteins are closely related to age-related neurodegeneration as seen in Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD)[1,2,3]
We found that the expression of α -syn was significantly increased in the substantia nigra par compacta (SNpc) of the PD mice group (PG) mouse brain (Fig. 1)
Several previous studies have shown that acupuncture at GB34 can protect the dopaminergic neuron against MPTP25–28
Summary
Aggregation-prone proteins, e.g. α -synuclein (α -syn), amyloid-β (aβ ), Tau and polyglutamine-containing proteins (poly Q) are closely related to age-related neurodegeneration as seen in Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD)[1,2,3]. Clearance of aggregation-prone proteins by enhancing the autophagic level holds great promise in therapeutic treatment for NDDs3,5. As a specific inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, rapamycin has proven to be a potent inducer of autophagy and used for the treatment of certain diseases[3,8]. It is highly desirable to develop safer therapeutic approaches that target downstream ALP in an mTOR-independent manner[3]. Given that the nature of acupuncture is mechanical stimulation, and that autophagy is closely related with many physical factors, e.g. starvation, exercise and mechanical stress[18,19], we were inspired to investigate the mechanism of acupuncture, the specificity of acupoints and PD treatment in a PD mouse model under the context of autophagic regulation
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