Parkinson’s disease (PD) is a neurodegenerative disorder. But not just. And it may not start that way.
There is increasing evidence that a-synuclein, the protein whose aggregates eventually destroy midbrain dopaminergic neurons in PD (and that are the cause of other diseases collectively known as the synucleinopathies), first aggregates “in enteric neurons, the neurons that control gastrointestinal function,” Collin Challis told BioWorld.
From there, a-syn aggregates can jump to the vagus nerve and travel into the brain via retrograde transport. Once there, they seed more aggregates, ultimately resulting in the death of midbrain dopaminergic neurons and the hallmark motor symptoms of PD.
In the Feb. 17, 2020, issue on Nature Neuroscience, Challis, who was a postdoctoral scholar at the California Institute of Technology at the time of the study, and his colleagues have demonstrated that increased peripheral expression of the enzyme glucocerebrosidase – better known for its role in the lysosomal storage disorder Gaucher disease – could reverse some of the effects of peripheral a-syn aggregates.
They also showed that while a-synuclein fibrils traveled centrally after they were injected into the duodenum in both young adult and aged mice, “only in old mice did it lead to motor pathology,” Challis said.
Collectively, the results suggest that it is possible, and beneficial, to identify Parkinson’s disease at the prodromal stage.
They also show that ameliorating PD symptoms is possible by improving cells’ general housekeeping abilities, rather than focusing on the lack of dopamine that leads to PD’s hallmark motor symptoms, or even the a-syn aggregates that kill the dopaminergic cells.
PD, Challis said, is “really a disease of aging, when you don’t have the proper systems in place to take care of these symptoms.”
Aging takes a toll, along with everything else, on the lysosome, a cell structure that is responsible for breakdown of multiple biomolecules from both inside and outside the cell. Intracellularly, unwanted and damaged proteins – including protein aggregates – are digested in the lysosome via autophagy.
Lysosomes produce multiple enzymes to carry out their role, and mutations in those enzymes can lead to dozens of rare diseases, collectively known as the lysosomal storage disorders. Those disorders are due to the toxic buildup of different metabolites, depending on which enzyme is out of commission.
One such disorder is Gaucher disease, which results from mutations in GBA1, the gene that codes for the enzyme glucocerebrosidase. Previous work had shown that patients with Gaucher disease are at increased risk of PD. It is also well established that PD leads to gastrointestinal as well as motor issues. Collectively, this prompted Challis and his colleagues to test whether increasing levels of glucocerebrosidase could prevent the spreading of alpha-synuclein aggregates, and the gut symptoms of PD.
They showed that delivering GBA1 via gene therapy to mice increased glucocerebrosidase levels and could reduce, though not eliminate, the pathological effects of seeding the animals with preformed a-syn aggregates.
In a separate set of experiments, they compared the effects of seeding in young adult and very old mice, and showed that the same seeding had worse effects in the aged animals, consistent with the idea that targeting processes that go awry in aging, rather than targeting a-syn or attempting to restore midbrain dopamine levels, could be a viable strategy in PD.
The idea that neurodegenerative disorders would benefit from early intervention is not a new one. In Alzheimer’s disease (AD), the idea that early intervention will allow anti-amyloid beta antibodies to show benefits has led to repeated cycles of testing drugs earlier and earlier in the disease course.
In AD, those attempts have been unsuccessful to date. However, they have also been narrowly focused on applying the same treatment – anti-amyloid antibodies – earlier in the disease course.
The work published by Challis, senior author Viviana Gradinaru and their colleagues takes a different, broader view of PD, and suggests that in Parkinson’s disease, it might be possible to forestall the disease before it reaches the brain.
The study exemplifies “the shift from focusing on the CNS alone,” Gradinaru, who is the director of the Center for Molecular and Cellular Neuroscience and professor of neuroscience and biological engineering at Caltech, told BioWorld. “If you deal with [a-synuclein] in the gut, maybe it won’t have a chance to progress to full pathology.”