Study Shows Age-dependent Spread Of Alpha-synuclein From Gut to Brain in Mice

Study Shows Age-dependent Spread Of Alpha-synuclein From Gut to Brain in Mice
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Aggregates of the Parkinson’s disease-associated protein alpha-synuclein can spread from the gut to the brain in mice, but this process is dependent on aging, likely as a result of altered protein dynamics, a new study suggests.

The study, “Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice,” was published in Nature Neuroscience.

Parkinson’s disease is characterized by aggregates of alpha-synuclein in the nervous system, particularly in dopamine-producing neurons in the brain. However, how these aggregates form in the first place isn’t fully understood.

One proposed hypothesis is that these aggregates don’t initially form in the brain, but in the enteric nervous system (ENS) — the nervous system of the gut. This hypothesis is supported by the fact that many people with Parkinson’s experience gastrointestinal symptoms, such as constipation, years before the onset of motor symptoms. The idea is that, from the gut, the aggregates could “spread up” to the brain through the vagus nerve.

“The vagus nerve is a physical connection between neurons in the gut and neurons in the brain,” study co-author Collin Challis, PhD, a former postdoctoral researcher at California Institute of Technology (Caltech), said in a press release. “If these damaging protein clusters first originate in gut neurons, then in the future we may be able to diagnose [Parkinson’s disease] earlier and potentially use gene delivery to restore functions to the cells so that they can clean up the aggregates.”

In the new study, researchers injected alpha-synuclein aggregates into the lining of the intestinal tract in mice. This led to numerous Parkinson’s-associated changes in the gut, including increased production of inflammatory molecules (e.g. IL-6), gastrointestinal dysfunction, and increased activation of neurons in the ENS, indicating an inflammatory response.

The researchers then looked to see whether the aggregates had spread into the central nervous system (CNS, comprising the brain and spinal cord). Interestingly, initial experiments did not reveal significant aggregate accumulation in the CNS, nor were there sustained motor impairments of the sort that would be expected if this system was modeling Parkinson’s disease.

But, crucially, these experiments were done in young adult mice (8-10 weeks old), and the biggest risk factor for developing Parkinson’s is aging. Thus, the researchers repeated the experiment in older (16-month-old) mice.

In these mice, as in the younger mice, injecting alpha-synuclein into the gut lining led to gut dysfunction. But, unlike in the young mice, older mice also developed motor deficits resembling Parkinson’s disease. Furthermore, the older mice did have alpha-synuclein aggregates in their brainstems, supporting the idea that the aggregates “spread up.”

Additionally, the older mice had significantly reduced levels of dopamine in their brains, which was not observed in the younger mice following alpha-synuclein injection.

The reason for this age-related difference may come down to how protein-regulating systems in the body change with age.

The researchers demonstrated that older mice express significantly less of the gene GBA1, which encodes for the protein glucocerebrosidase (GCase). This protein plays a critical role in the molecular machinery that cells use to recycle proteins, so the researchers proposed that the age-associated decrease in GCase levels could allow alpha-synuclein aggregates to spread in a way that is limited in younger animals.

In keeping with this idea, the researchers found that, when they increased GCase levels in the guts of young adult mice through gene therapy using a variant of adeno-associated virus (AAV) as a delivery system, gut-related problems associated with alpha-synuclein were diminished, though not entirely resolved. As such, although GCase dysfunction probably isn’t the only factor, it likely plays a role in alpha-synuclein pathology.

“Our results propose mechanisms that may underlie the etiology of sporadic [Parkison’s disease] and highlight GBA1 as a therapeutic target for prodromal [early], peripheral synucleinopathy,” the researchers wrote.

“Interestingly,” they noted, “[disease-causing alpha-synuclein] also inhibits GCase function.” As such, it’s possible that there is a feedback loop wherein increasing alpha-synuclein leads to decreased GCase function, which in turn leads to further increases in alpha-synuclein, until a threshold is crossed, spilling over into disease.

“Mutations in the gene that encodes GCase are responsible for Gaucher disease and a risk factor in [Parkinson’s disease],” said Viviana Gradinaru, PhD, a professor at Caltech and co-author of the study. “Our work shows that this gene can be delivered by AAVs to rescue gastric symptoms in mice, and emphasizes that peripheral neurons are a worthwhile target for treating [Parkinson’s disease], in addition to the brain.”

Overall, the researchers said, “[O]ur findings suggest that age-related declines in protein homeostasis, including diminished GCase function, may promote susceptibility to [disease causing alpha-synuclein] in the ENS and support the gut-to-brain hypothesis of [the biology of] synucleinopathy.”

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
Total Posts: 208
Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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