Gut Hormones Restrict Neurodegeneration in Parkinson’s Disease

Abstract

Parkinson’s disease is the most common neurodegenerative movement disorder and the second most common neurological disorder behind Alzheimer’s disease in today’s society. It is a progressive disorder that affects more than 1% of people older than 60. Cardinal features of Parkinson’s disease include motor dysfunction such as rigidity, resting tremor, postural instability and bradykinesia. These debilitating symptoms manifest due to the massive loss of dopamine in the striatum, the nerve terminal region of dopamine neurons are located in the substantia nigra pars compacta (SNpc). This anatomical circuit is known as the nigrostriatal pathway and plays a critical role in fine tuning motor functions. At present there are only a few known monogenic mutations accelerating the onset of Parkinson’s disease, therefore most cases are considered sporadic and develop as a complex polygenic interaction with age and environment. Although the pathogenesis of Parkinson’s disease is largely unknown, mitochondrial dysfunction, oxidative stress, intracellular protein accumulation (Lewy Bodies containing α-synuclein) and abnormal protein degradation all play a key role in disease progression. Because loss of dopamine in the striatum causes motor dysfunction in Parkinson’s disease, dopamine supplementation can be used to alleviate motor symptoms but this is only a temporary solution as the efficacy diminishes with age and as the disease progresses. There are no known therapies that halt or reduce the progression of the disease, largely because the cause of Parkinson’s disease remains enigmatic. Parkinson’s disease also causes symptoms in other parts of the nervous system. Constipation and gastrointestinal (GI) problems are often some of the earliest symptoms, well before the presence of dopamine dysfunction, and post mortem studies in Parkinson’s disease patients identified protein accumulation in the enteric nervous system of the GI tract [1]. This ‘Braak’s hypothesis’ suggests protein accumulation in enteric neurons spreads in a retrograde manner to the brain through the dorsal motor nucleus of the vagus and triggers Parkinson’s disease. Braak observed in post mortem tissue that patients with presymptomatic Parkinson’s disease had protein aggregation in the peripheral nervous system but not the central nervous system [1]. Protein aggregation ascended into the central nervous system and correlated with the development of motor dysfunction. This observation shows that the topographic ascending lesion pattern resembles a falling row of