Pre-clinical study suggests Parkinson’s could start in the gut.

Parkinson’s disease is a progressive neurodegenerative disorder exhibiting far-reaching clinical manifestations, with recent research focusing on gut-brain interactions involving the gut microbiota.  However, researchers understand little about the link between this gut-brain axis and Parkinson’s.  Now, a study led by researchers from Duke University identifies alpha-synuclein, a protein implicated in Parkinson’s, inside endocrine cells populating the small intestines.  The team states an agent in the gut might interfere with this alpha-synuclein, deforming the protein, allowing it to spread to the central nervous system (CNS) as a prion, an infectious protein.  The opensource study is published in the journal JCI Insight.

Previous studies show misfolded α-synuclein is found in enteric nerves before it appears in the brain, suggesting a model where Parkinson’s disease originates in the gut and spreads to the CNS via cell-to-cell prion-like propagation.  There is abundant evidence misfolded alpha-synuclein is found in the nerves of the gut before it appears in the brain, however, exactly where this misfolding occurs is unknown.  Past studies from the lab showed endocrine cells in the gut epithelium also possess neuron-like properties, connecting to the enteric nerves to provide a pathway of communication with the brain, as shown in this time-lapse video.  The current study shows α-synuclein is expressed in endocrine cells in both the mouse and human intestine.

The current study utilizes cultured enteroendocrine cells of the mouse and human intestine expressing α-synuclein.  Results show α-synuclein–containing endocrine cells in the gut directly connect to α-synuclein–containing nerves, forming a neural circuit between the gut and the nervous system.  Data findings show α-synuclein is also expressed in enteric nerves and to a lesser extent in enteric glia.

The lab explains toxins or other environmental influences in the gut lumen may affect α-synuclein folding in these endocrine cells, thereby beginning a process where misfolded α-synuclein could propagate from the gut epithelium to the brain.  They go on to add their findings proffer a working explanation of how malformed proteins can spread from the inside of the intestines to the nervous system, using a non-nerve cell acting as a nerve.

The team surmises their study shows α-synuclein is expressed in mouse and human enteroendocrine cells in the gut where they form a neural circuit with the nervous system.  For the future, the researchers state they now plan to examine the gut endocrine cells from people with Parkinson’s to see if they contain misfolded and/or abnormal alpha-synuclein.

Source: Duke University

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