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?-Synuclein in gut endocrine cells and its implications for Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disease with devastating clinical manifestations. In PD, neuronal death is associated with intracellular aggregates of the neuronal protein ?-synuclein known as Lewy bodies. Although the cause of sporadic PD is not well understood, abundant clinical and pathological evidence show that misfolded ?-synuclein is found in enteric nerves before it appears in the brain. This suggests 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 ?-synuclein initiates misfolding of native ?-synuclein in recipient cells. We recently discovered that enteroendocrine 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. In this report, we demonstrate that ?-synuclein is expressed in the EEC line, STC-1, and native EECs of mouse and human intestine. Furthermore, ?-synuclein-containing EECs directly connect to ?-synuclein-containing nerves, forming a neural circuit between the gut and the nervous system in which toxins or other environmental influences in the gut lumen could affect ?-synuclein folding in the EECs, thereby beginning a process by which misfolded ?-synuclein could propagate from the gut epithelium to the brain.

SUBMITTER: Chandra R

PROVIDER: S-EPMC5470880 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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α-Synuclein in gut endocrine cells and its implications for Parkinson's disease.

Chandra Rashmi R Hiniker Annie A Kuo Yien-Ming YM Nussbaum Robert L RL Liddle Rodger A RA

JCI insight 20170615 12

Parkinson's disease (PD) is a progressive neurodegenerative disease with devastating clinical manifestations. In PD, neuronal death is associated with intracellular aggregates of the neuronal protein α-synuclein known as Lewy bodies. Although the cause of sporadic PD is not well understood, abundant clinical and pathological evidence show that misfolded α-synuclein is found in enteric nerves before it appears in the brain. This suggests a model in which PD pathology originates in the gut and spr ...[more]

PMID: 28614796

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Project description:The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years in identifying disease-modifying therapies for Parkinson's disease that target alpha-synuclein. However, these treatments have not yet shown clear efficacy in slowing the progression of this disease. Several explanations exist for this issue. The pathogenesis of Parkinson's disease is complex and not yet fully clarified and the heterogeneity of the disease, with diverse genetic susceptibility and risk factors and different clinical courses, adds further complexity. Thus, a deep understanding of alpha-synuclein physiological and pathophysiological functions is crucial. In this review, we first describe the cellular and animal models developed over recent years to study the physiological and pathological roles of this protein, including transgenic techniques, use of viral vectors and intracerebral injections of alpha-synuclein fibrils. We then provide evidence that these tools are crucial for modelling Parkinson's disease pathogenesis, causing protein misfolding and aggregation, synaptic dysfunction, brain plasticity impairment and cell-to-cell spreading of alpha-synuclein species. In particular, we focus on the possibility of dissecting the pre- and postsynaptic effects of alpha-synuclein in both physiological and pathological conditions. Finally, we show how vulnerability of specific neuronal cell types may facilitate systemic dysfunctions leading to multiple network alterations. These functional alterations underlie diverse motor and non-motor manifestations of Parkinson's disease that occur before overt neurodegeneration. However, we now understand that therapeutic targeting of alpha-synuclein in Parkinson's disease patients requires caution, since this protein exerts important physiological synaptic functions. Moreover, the interactions of alpha-synuclein with other molecules may induce synergistic detrimental effects. Thus, targeting only alpha-synuclein might not be enough. Combined therapies should be considered in the future.

Dataset Information

?-Synuclein in gut endocrine cells and its implications for Parkinson's disease.

Publications

α-Synuclein in gut endocrine cells and its implications for Parkinson's disease.

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