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 body via the 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 by in 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.

Keywords: Braak’s hypothesis; Lewy pathology; Parkinson’s disease; enteric nervous system; αSynuclein.

Figure 1

A schematic representation of the Braak’s hypothesis of Parkinson’s disease (PD). Microbial products come into contact with olfactory and/or enteric neurons, which trigger the aggregation of α-Synuclein (1 and 2). The aggregated α-Synuclein spreads toward the central nervous system via the olfactory bulb and the vagus nerve (3 and 4). Eventually, the aggregated α-Synuclein arrives at the substantia nigra (5). Genetic factors are likely to contribute to PD, but the exact mechanism remains to be elucidated (6).