title: Exploring Braak's Hypothesis of Parkinson's Disease.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder for which there is no cure. Most patients suffer from sporadic PD, which is likely caused by a combination of genetic and environmental factors. Braak's hypothesis states that sporadic PD is caused by a pathogen that enters the bodyviathe nasal cavity, and subsequently is swallowed and reaches the gut, initiating Lewy pathology (LP) in the nose and the digestive tract. A staging system describing the spread of LP from the peripheral to the central nervous system was also postulated by the same research group. There has been criticism to Braak's hypothesis, in part because not all patients follow the proposed staging system. Here, we review literature that either supports or criticizes Braak's hypothesis, focused on the enteric route, digestive problems in patients, the spread of LP on a tissue and a cellular level, and the toxicity of the protein αSynuclein (αSyn), which is the major constituent of LP. We conclude that Braak's hypothesis is supported byin vitro, in vivo, and clinical evidence. However, we also conclude that the staging system of Braak only describes a specific subset of patients with young onset and long duration of the disease.
authors.affiliation: Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Utrecht , Netherlands.
authors.forename: Carmen D
authors.initials: CD
authors.lastname: Rietdijk
authors.affiliation: Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Utrecht , Netherlands.
authors.forename: Paula
authors.initials: P
authors.lastname: Perez-Pardo
authors.affiliation: Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands; Nutricia Research, Utrecht, Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.affiliation: Department of Biomedical Signals and Systems, MIRA, University of Twente, Enschede, Netherlands; Department of Biophysics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, Netherlands.
authors.forename: Richard J A
authors.initials: RJ
authors.lastname: van Wezel
authors.affiliation: Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Utrecht , Netherlands.
authors.forename: Aletta D
authors.initials: AD
authors.lastname: Kraneveld
keywords: Braak’s hypothesis; Lewy pathology; Parkinson’s disease; enteric nervous system; αSynuclein