The Gut-Brain Axis Based on α-Synuclein Propagation-Clinical, Neuropathological, and Experimental Evidence

The cytopathological hallmark of Parkinson's disease (PD) is a neuronal cytoplasmic inclusion called Lewy body (LB). Lewy bodies are composed of alpha-synuclein (aSyn), a 140 aa protein that is predominantly expressed in the presynaptic terminal and which is implicated in neurotransmitter release. Recently, aSyn was found to propagate from neuron to neuron in a trans-synaptic manner. Although the precise molecular mechanisms are unclear, the propagation of aSyn is believed to play a major role in the progression of Lewy pathology in PD. Neuropathologically, the initial Lewy pathology has been shown to be formed in the dorsal motor nucleus of the vagus (DMV) or olfactory bulb by neuropathological studies. Since the DMV innervates the enteric nervous system (ENS) and LBs are formed in the gut nerve plexuses, it is conceivable that LBs propagate from the gut to the DMV and then to other regions of the brain. In this article, clinical, neuropathological, and experimental evidence supporting or negating the idea that aSyn propagation from the ENS to the brain leads to PD is reviewed. Moreover, the propagation of aSyn seeds through systemic circulation or multifocal generation of aSyn seeds is discussed as a potential alternative scenario for aSyn spreading.