Peripheral alpha-synuclein and Parkinson's disease

Alpha-synuclein (a-syn) has been implicated in the etiopathogenesis of Parkinson’s disease (PD) based on the observation that mutations in the protein cause a familial form of the disease. That duplication and triplication of the wild type gene can also lead to a familial form of PD suggests that increased expression of the normal protein is itself sufficient to cause the disease. The observation that Lewy pathology is found in formerly healthy young dopamine neurons that have been implanted into the striatum of PD patients has raised the possibility that a-syn is a prion and that PD is a prion disorder. In support of this concept, it has now been demonstrated that a-syn can be taken up dopamine neurons in both transgenic and wild type rodents leading to inclusion body formation, neurodegeneration, behavioral abnormalities and transfer/ transport to neighboring regions with extension of the disease process (reviewed in reference 2). In PD, there has been considerable interest in the possibility that this sequence might begin in the periphery and specifically in the GI system where it is postulated that a-syn pathology might initiate and then spread to involve brain stem structures. Confirmation of this concept would greatly enhance our understanding of the nature of the PD pathologic process, provide novel targets for a neuroprotective therapy and offer the opportunity to identify a biomarker for diagnosing patients at an early or prodromal stage of the disease. Indeed, it may be necessary to introduce a neuroprotective strategy at an early stage as recent studies suggest that dopamine neuronal degeneration is largely complete within a few years of diagnosis based on the traditional motor features. While a-syn pathology in the SNc is widely used as the seminal post-mortem diagnostic marker for confirmation of the clinical diagnosis of PD, it is now wellappreciated that a-syn pathology is also present within multiple structures in the brain, spinal cord and peripheral autonomic nervous system of PD patients, and specifically within the GI system. Indeed, a-syn pathology has been reported on colonic biopsies from asymptomatic individuals who years later went on to develop PD. This supports the Braak hypothesis which proposes that a-syn pathology spreads in a predictable and sequential manner, affecting the dorsal motor nucleus (DMN) of the vagus nerve at an early stage of the disease and only involving the SNc in a mid-stage of the illness. Terminals of the dorsal motor nucleus reside in the submucosal layer of the GI tract, mere millimeters from the lumen. This raises the possibility that exposure to a toxin or infectious agent could initiate a-syn accumulation and aggregation in the periphery with subsequent spread to the central nervous system (CNS.). These observations are consistent with epidemiologic studies indicating that constipation is a risk factor for PD, and may in fact represent a prodromal phase of the disorder. Accordingly there has been great interest in determining if asyn pathology can be detected in the GI system prior to the onset of the classic motor features of PD. Several articles published in the current and recent issues of Movement Disorders provide information relevant to the concept that pathologic a-syn might initially be expressed in the GI system, and may serve as a nidus for transmission to the DMN and other brain stem and cerebral structures. Confirmation of this hypothesis would have great importance for defining a potential biomarker of the disease for early diagnosis and for better understanding the nature of the origin of PD pathology.