Gut neuropeptide involvement in Parkinson’s disease

Apr 25, 2025American journal of physiology. Gastrointestinal and liver physiology

Role of gut nerve-signaling molecules in Parkinson's disease

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Abstract

Parkinson's disease affects over 10 million people globally.

Accumulation of misfolded α-synuclein protein in the substantia nigra is a key feature of Parkinson's disease.
Aggregated α-synuclein can form Lewy bodies, contributing to the degeneration of dopaminergic neurons and motor symptoms.
α-synuclein aggregates have been found in the gastrointestinal tract, suggesting a connection to nonmotor symptoms of Parkinson's disease.
GI symptoms can appear up to 20 years before motor symptoms, indicating communication between the central and enteric nervous systems.
Dysregulation of gut neuropeptide signaling is linked to pathological effects of Parkinson's disease in animal models.
The roles of gut neuropeptides in Parkinson's disease pathogenesis and modulation remain underexplored.

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Parkinson's disease (PD) is a neurodegenerative disorder affecting over 10 million people. A key pathological feature of PD is the accumulation of misfolded α-synuclein (aSyn) protein in the substantia nigra pars compacta. Aggregation of aSyn can form Lewy bodies that contribute to dopaminergic neuron degeneration and motor symptoms, such as tremor, rigidity, and bradykinesia. Beyond the central nervous system, aSyn aggregates have been detected in the gastrointestinal (GI) tract, suggesting a link between peripheral aSyn and nonmotor PD symptoms. GI symptoms, often preceding motor symptoms by up to 20 years, highlight the bidirectional communication between the central nervous system and the enteric nervous system (gut-brain axis) in PD. Although microbiome alterations and intestinal inflammation have been associated with PD, functional impacts on gut-brain signaling or aSyn aggregation remain unclear. Intestinal neuropeptides are key modulators of gut-brain communication, alter immune response to pathogens and environmental toxins, and may contribute to the function of the luminal gut barrier. Dysregulation of gut neuropeptide signaling, including vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide, ghrelin, cholecystokinin, glucagon-like peptide 1, and substance P, have been associated with pathologic effects of PD in animal models. Despite their potential role in pathogenesis and disease modulation, gut neuropeptide roles in PD are underexplored. This article reviews current knowledge surrounding microbial metabolite and immune influences on gut neuropeptide signaling, aSyn aggregation in the enteric nervous system, and downstream neuroimmune pathway alterations within the context of PD and its mouse models.

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Gut neuropeptide involvement in Parkinson’s disease

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