Digesting recent findings: gut alpha-synuclein, microbiome changes in Parkinson's disease.

Two hallmarks of Parkinson's disease (PD) are the widespread deposition of misfolded alpha-synuclein (αSyn) protein in the nervous system and loss of substantia nigra dopamine neurons. Recent research has suggested that αSyn aggregates in the enteric nervous system (ENS) lead to prodromal gastrointestinal (GI) symptoms such as constipation in PD, then propagating to the brain stem and eventually triggering neurodegeneration and motor symptoms. Additionally, whether the microbiome changes in PD contribute to the primary pathogenesis or, alternatively, are consequential to either the disease process or medication is still unclear. In this review, we discuss the possible roles of αSyn and microbiome changes in the GI system in PD and consider if and how the changes interact and contribute to the disease process and symptoms.

Anis E ，Xie A ，Brundin L ，Brundin P ... -  《-》

Nigral overexpression of α-synuclein in a rat Parkinson's disease model indicates alterations in the enteric nervous system and the gut microbiome.

A hallmark feature of Parkinson's disease (PD) is the build-up of α-synuclein protein aggregates throughout the brain; however α-synuclein is also expressed in enteric neurons. Gastrointestinal (GI) symptoms and pathology are frequently reported in PD, including constipation, increased intestinal permeability, glial pathology, and alterations to gut microbiota composition. α-synuclein can propagate through neuronal systems but the site of origin of α-synuclein pathology, whether it be the gut or the brain, is still unknown. Physical exercise is associated with alleviating symptoms of PD and with altering the composition of the gut microbiota. This study investigated the effects of bilateral nigral injection of adeno-associated virus (AAV)-α-synuclein on enteric neurons, glia and neurochemistry, the gut microbiome, and bile acid metabolism in rats, some of whom were exposed to voluntary exercise. Nigral overexpression of α-synuclein resulted in significant neuronal loss in the ileal submucosal plexus with no change in enteric glia. In contrast, the myenteric plexus showed a significant increase in glial expression, while neuronal numbers were maintained. Concomitant alterations were observed in the gut microbiome and related bile acid metabolism. Voluntary running protected against neuronal loss, increased enteric glial expression, and modified gut microbiome composition in the brain-injected AAV-α-synuclein PD model. These results show that developing nigral α-synuclein pathology in this PD model exerts significant alterations on the enteric nervous system (ENS) and gut microbiome that are receptive to modification by exercise. This highlights brain to gut communication as an important mechanism in PD pathology.

O'Donovan SM ，Crowley EK ，Brown JR ，O'Sullivan O ，O'Leary OF ，Timmons S ，Nolan YM ，Clarke DJ ，Hyland NP ，Joyce SA ，Sullivan AM ，O'Neill C ... -  《-》

Exploring the Connection Between the Gut Microbiome and Parkinson's Disease Symptom Progression and Pathology: Implications for Supplementary Treatment Options.

Chan DG ，Ventura K ，Villeneuve A ，Du Bois P ，Holahan MR ... -  《-》

Is Gut Dysbiosis an Epicenter of Parkinson's Disease?

Rajput C ，Sarkar A ，Sachan N ，Rawat N ，Singh MP ... -  《-》

Implications of the Gut Microbiome in Parkinson's Disease.

Parkinson's disease is a common neurodegenerative disorder that presents with nonmotor and motor symptoms. The nonmotor manifestations of Parkinson's disease often begin years before the motor symptoms. Autopsy studies, including both Parkinson's disease patients and matched controls, demonstrated that α-synuclein aggregates in Parkinson's disease patients can be found in both the substantia nigra and the enteric nervous system. Therefore, it has been hypothesized that the pathological process that leads eventually to Parkinson's disease might initially take place in the enteric nervous system years before the appearance of motor features. The gut microbiome plays essential roles in the development and maintenance of different body systems. Dysbiosis of the normal gut microbiome is thought to be associated with pathophysiologic changes not only in the gastrointestinal system itself but also in the enteric and central nervous systems. These changes are thought to ultimately cause loss of dopaminergic neurons via various mechanisms including the release of neurotoxins into the systemic circulation, decreased production of neuroprotective factors, and triggering inflammatory and autoimmune responses. In this review, we review the gut microbiome changes in Parkinson's disease and discuss the mechanisms by which gut microbiome dysbiosis may be a contributing factor to the pathophysiology of Parkinson's disease. © 2020 International Parkinson and Movement Disorder Society.

Elfil M ，Kamel S ，Kandil M ，Koo BB ，Schaefer SM ... -  《-》