Targeting the Gut-Brain axis in Parkinson's disease

Abstract

Parkinson’s disease (PD) is the most common progressive movement disorder, with increasing age being the greatest risk factor for its development. PD is hallmarked by the progressive degeneration of dopaminergic nigrostriatal neurons, with reductions in striatal dopamine levels resulting in the characteristic motor impairments. Another characteristic of PD is alpha-synuclein containing inclusion bodies in the surviving neurons in different areas of the central and peripheral nervous system There are two forms of PD; familial and sporadic. The familial form is caused by genetic aberrations, but the causes of sporadic PD onset remain unknown. However, some progress has been made in the search for potential causes and it is thought that it probably has multifactorial origins, with contributions from genetic predisposition, environmental factors, and aging. The early involvement of the gastrointestinal tract in PD supports the hypothesis that environmental factors could exert its influence on PD development and progression via the gut. This thesis provides evidence for the occurrence of motor symptoms and GI dysfunction in two separate rotenone-induced PD mouse models. The models suggest a bidirectional gut-brain communication involved in the genesis of PD-like phenotype where TLR4-mediated gut inflammation and changes in microbiota composition may play an important role. A nutritional intervention containing phospholipid precursors, cofactors, and prebiotic fibers has been proven effective in the treatment after disease induction of motor and non-motor symptoms in the rotenone model. Moreover, the diet shows an additive effect to levodopa, the most commonly used drug in the treatment of PD. Hence, this specific diet may result in a beneficial treatment for PD when combined with the oral levodopa treatment. Combined, the findings in this thesis create more insight into the pathophysiological relevance of gut-brain interactions in PD and demonstrate that the nutritional intervention may be beneficial in the prevention but also the management of the disease.