Parkinson disease (PD) is a debilitating neurodegenerative disease characterized by motor disturbances –– including resting “pill-rolling” tremor, cogwheel rigidity, and slow movements, as well as gastrointestinal symptoms, such as constipation and gastroparesis (decreased ability of stomach to move food to the small intestine). PD’s pathological hallmarks are cytoplasmic inclusions known as Lewy bodies (within the cell body) and Lewy neurites (in axons) of the brain and enteric nervous system. These inclusions are associated with degeneration of dopaminergic neurons in the substantia nigra pars compacta (region of the brain), which produces the distinctive disorders of movement and vagal nerve dysfunction.
The major component of Lewy pathology is aggregated α-synuclein, a synaptic protein with the propensity to misfold and aggregate. Misfolded α-synuclein plays a critical role in PD pathogenesis, and recent evidence supports a model in which propagation of Lewy pathology occurs via cell-to-cell transmission of misfolded α-synuclein onto recipient cells. Misfolded α-synuclein recruits native α-synuclein in the recipient cell and acts as a template for development of aggregates that eventually lead to formation of Lewy bodies and, ultimately, PD. Although pathogenesis of PD is not well understood, recent studies have suggested the pathological process begins in the enteric nervous system (of the intestine), and both clinical and experimental-animal data support such a model.
Realization of the importance of the “brain-gut-microbione” has greatly expanded during the past decade. Microbes in the gastrointestinal (GI) tract are now appreciated to provide each os us, as “hosts”, with countless beneficial functions (e.g. contributions to vitamin supplementation, food digestion, and defense against pathogens of all kinds). The “microbiome” interacts with the host organism’s genome and physiology –– by way of direct contact through surface antigens, intracellular transfer of certain molecules, and soluble molecules produced by bacterial metabolism (detectable by metabolomics).
There is clearly bi-directional communication between the GI tract and the central nervous system (CNS), which also provides communication-pathways between intestinal microbiota and the host’s neural circuitry including the CNS. Modulation of GI-tract and CNS function via the microbiome is now recognized to include such ill-defined traits as “behavior,” cognitive functions, “mood,” “suicidal tendencies,” “obsessive-compulsive disorder,” appetite, and autism spectrum disorder. Production of bioactive compounds by microbiota and their potential probiotic activities consists of neuroactive molecules –– e.g. histamine, serotonin, catecholamines, and trace amines.
Authors [see attached paper] describe abundant clinical and pathological evidence that show misfolded α-synuclein is found in enteric nerves BEFORE it appears in the brain; these findings suggest a model in which PD pathology originates in the gut and spreads to the central nervous system via cell-to-cell prion-like propagation, such that transfer of misfolded α-synuclein initiates misfolding of native α-synuclein in recipient cells. [Prions are infectious proteins that act like viruses, but lack DNA or RNA. Discovery of prions was so unexpected that it remained controversial for ~25 years before a Nobel Prize (1997) was given to the single discoverer, Stan Prusiner. Prions are ubiquitous, occurring in yeast as well as mammals and belived to be the agent that causes scrapie and other degenerative diseases of the CNS.]
Authors [attached article] recently discovered that entero-endocrine cells (EECs) –– which are part of the gut epithelium and directly face the gut lumen –– also possess many neuron-like properties and connect to enteric nerves. Herein, authors show that α-synuclein is expressed in the EEC line, STC-1, as well as native EECs of mouse and human intestine. Moreover, α-synuclein–containing EECs directly connect to α-synuclein–containing nerves, forming a neural circuit between the gut and the CNS in which toxicants, or other environmental adversities, in the gut lumen could affect α-synuclein folding in the EECs, thereby beginning a process by which misfolded α-synuclein could propagate from the gut epithelium to the brain. Very cool findings, which would’ve been completely unexpected a decade ago. Today, given our knowledge of the brain-gut-microbiome and its importance to clinical health, these data make a lot more sense.
JCI Insight 15 June 2017; 2:. pii: 92295. doi: 10.1172/jci.insight.92295. [Epub ahead of print] PMID: 28614796
COMMENT: David Perlmutter’s books Grain Brain and Brain Maker are fantastic on topic, but the problem has always been finding studies that are not merely correlations between gluten sensitivity and neurodegeneration. This is amazing! Thank you Dan for describing/sharing.