Summary: Researchers are using the transparent worm C. elegans to investigate the growing hypothesis that Parkinson’s disease can begin in the gut and later spread to the brain.
Source: Medical College of Georgia at Augusta University
A tiny roundworm, Caenorhabditis elegans (C. elegans), is helping scientists probe an increasingly studied idea: Parkinson’s disease may originate in the gastrointestinal tract before reaching the brain.
Parkinson’s disease is widely recognized for its motor symptoms such as tremors, but cognitive decline and gastrointestinal problems like constipation are also common. Central to the disease is alpha-synuclein, a protein that can misfold and form sticky, toxic aggregates. These aggregates — often referred to as Lewy bodies — disrupt neuronal function and can lead to cell death.
Evidence from laboratories including that of neuroscientist Danielle Mor, PhD, suggests these toxic alpha-synuclein aggregates can appear in neurons of the gut before they are detected in the brain. Indeed, Lewy bodies have been observed on autopsy within neurons in the gut wall of people with early Parkinson’s, supporting the gut-first hypothesis.
“This is now a hot area of research,” says Mor, a faculty member in the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia. “Intervening at the gut stage offers an exciting and potentially earlier window for therapy.”
Neurons in the gut and brain are in constant communication, but precisely how alpha-synuclein becomes pathological in both locations remains unclear. In animal models, researchers have observed aggregates being released from one neuron and taken up by the next, and in some cases traveling from the gut up the spinal cord into the brain. This transfer appears to occur mainly along existing neural connections.
Mor recently received a two-year, $400,000 Early-Investigator Research Award from the U.S. Department of Defense to study how gut-derived alpha-synuclein affects cognition, how the protein enters neurons, and whether any existing drugs can mitigate its cognitive effects.
Mor is among the first to directly examine how alpha-synuclein in the gut influences learning and memory. Her choice of C. elegans as a model is deliberate: these transparent nematodes share a substantial portion of their gene repertoire with humans, possess a digestive tract, and use many of the same neurotransmitters, including acetylcholine and dopamine.
Dopamine depletion is a hallmark of Parkinson’s and is closely linked to the motor symptoms of the disease. A healthy balance between dopamine and acetylcholine is important for coordinated movement and for cognitive processes like learning. Because C. elegans has an alimentary nervous system — a gut-based network of neurons that manages digestion and nutrient absorption — it provides a practical system to model early, gut-localized alpha-synuclein aggregation.
“We are modeling gut-to-brain alpha-synuclein transmission, which we believe is one possible route for disease progression in humans,” Mor explains. “Once we establish transmission, we can test learning and memory in these worms.”
Earlier worm models engineered alpha-synuclein expression in neuronal tissue resembling the brain. Mor’s approach was to feed C. elegans a toxic human form of the protein. Within days she observed the protein spreading to different tissues, degeneration of dopamine-producing neurons, and motor impairments. For a species with a lifespan of only two to four weeks, those changes occur rapidly.
With her new funding, Mor is emphasizing cognitive effects that typically arise later in Parkinson’s. Despite their simplicity, C. elegans can perform associative learning tasks, which provides a measurable readout of cognitive function. In Mor’s experiments, worms learn to associate a distinctive scent — butanone — with food (bacteria). This association forms quickly, yielding a short-term memory that can be tested by observing whether worms move toward the scent.
One primary question is whether feeding worms the toxic alpha-synuclein aggregates diminishes their ability to form or recall these associations. Preliminary observations suggest that gut-derived aggregates that reach the nervous system impair motor and, potentially, cognitive function.
Mor’s lab is also investigating how alpha-synuclein enters gut neurons. Cell culture studies indicate the toxic protein may bind to cell surface sugar chains called proteoglycans, which act like receptors facilitating uptake. By selectively reducing expression of genes involved in proteoglycan synthesis, her team has already reduced dopamine neuron damage and alleviated some disease symptoms in worms.
“We believe we are blocking alpha-synuclein from entering cells,” Mor says. Her current work involves systematically knocking down 17 genes in the proteoglycan pathway to identify which are critical for uptake and toxicity.
To accelerate therapeutic development, Mor is conducting high-throughput screens of FDA-approved drugs. Instead of targeting alpha-synuclein itself, she seeks compounds that counteract the downstream cellular toxicity that leads to disrupted metabolism and neuronal death. While other groups are developing monoclonal antibodies against alpha-synuclein, those approaches remain under evaluation.
Mor’s worm models complement mouse models that use a similar gut-to-brain framework. Compared with mice, C. elegans offers faster, large-scale manipulations that are well suited to genetic screening and high-throughput drug testing.
Alpha-synuclein’s normal role is not fully defined, but the protein is abundant in neurons and appears to help manage vesicles — small cellular compartments that carry neurotransmitters and support neuronal communication. When alpha-synuclein misfolds and aggregates, this essential function is disrupted, contributing to neuronal dysfunction and death.
The gut-to-brain pathway aligns with the possibility that environmental exposures — through food, water, or certain occupational settings — could trigger alpha-synuclein pathology. Alternatively, disturbances in the gut microbiome caused by diet, medication, or stress might encourage harmful protein changes. Mor emphasizes that multiple mechanisms could lead to pathogenic alpha-synuclein aggregation.
Clinically, cognitive decline in Parkinson’s tends to appear later and varies widely among patients. Other early non-motor symptoms can include loss of smell and sleep disturbances.
Mor’s new grant is supported by mentorship from physician-scientist Chandramohan Wakade, MBBS, associate dean for research at the AU College of Allied Health Sciences, and Erhard Bieberich, PhD, a biochemist at the University of Kentucky College of Medicine.
About this Parkinson’s disease research news
Author: Toni Baker
Source: Medical College of Georgia at Augusta University
Contact: Toni Baker – Medical College of Georgia at Augusta University
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