Targeting Diet-Microbiome Interactions in the Pathogenesis of Parkinson s Disease
Abstract
Neurological dysfunction is the basis of many human diseases. Behavioral, psychiatric, and neurodegenerative disorders often display hallmark abnormalities within the central nervous system (CNS). One such neuropathology, called amyloidosis, results from aberrant aggregation of specific neuronal proteins that disrupt many cellular functions. Affected tissues often contain insoluble aggregates of proteins that display altered conformations, a feature believed to contribute to an estimated 50 distinct human diseases. Neurodegenerative amyloid disorders, including Alzheimer’s, Huntington’s, and Parkinson’s disease (PD), are each associated with a distinct amyloid protein. PD is the second most common neurodegenerative disease in the United States, affecting an estimated 1 million people in the US, and 1% of the population over 60 years of age. Worldwide, about 10 million patients suffer from the often-debilitating symptoms of PD, which involve motor deficits including tremors, muscle rigidity, bradykinesia, and impaired gait. It is a multifactorial disorder that has a strong environmental component, as less than 10% of cases are hereditary (i.e., have a genetic basis). Further, treatment options are limited, and often have severe side effects. Therefore, discovery of safe and effective therapeutics are needed to address the increasing burden of PD in an ever-aging population. The human body is permanently colonized by microbes on virtually all environmentally exposed surfaces, the majority of which reside within the intestines. Mounting evidence over the past decade has suggested that the gut microbiome critically controls the development and function of the immune and metabolic systems. Increasingly, new research is beginning to uncover the profound impacts that gut bacteria can have on neurodevelopment and the CNS. Although most neurological diseases have been historically studied as disorders of the brain, non-CNS influences have been implicated. Research in several neurological diseases have found close interactions between the gut-associated immune system, enteric nervous system (ENS) and gut-based endocrine system; however, these findings have largely been overlooked by the mainstream neuroscience community. Indeed, emerging data suggest bidirectional communication between the gut and the brain in anxiety, depression, nociception, and autism spectrum disorder, among others. Gastrointestinal (GI) physiology and motility are influenced by signals arising both locally within the gut and from the CNS. Neurotransmitters, immune signaling, hormones, and neuropeptides produced within the gut may, in turn, impact the brain. Intriguingly, subjects with PD exhibit intestinal inflammation, and constipation often precedes motor defects by many years. Braak’s hypothesis posits that PD pathophysiology initiates in the gut and propagates to the brain. However, the notion that disease starts in the ENS and spreads to the CNS remains controversial, and experimental support for a gut microbial connection to PD is lacking. Research into how the gut-brain axis influences neurological conditions may reveal insights into disease etiology. This research program directly addresses the Fiscal Year 2016 Parkinson’s Research Program Focus Area on the effects of the microbiome and the GI tract on PD. Upon completion, our research will determine molecular mechanism(s) by which the gut microbiome contributes to hallmark PD symptoms. We speculate that understanding how the gut microbiome contributes to the pathogenesis of PD may lead to dietary, prebiotic, and probiotic treatments for patients with sporadic, non-hereditary cases. The clinical benefits may include safe and easy to administer oral treatments, that have durable efficacy (unlike current drugs such as L-DOPA) and are non-invasive (unlike deep brain stimulation; DBS). Further, treatments will likely be affordable as production costs for probiotic bacteria and pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710588
Entities
People
- Viviana Gradinaru
Organizations
- California Institute of Technology
- United States Army