BOSTON -- Research exploring associations between Gaucher's disease and certain aspects of Parkinson's disease offers a promising new approach to possibly preventing or treating the latter, a researcher said here.
In particular, diminished activity of glucocerebrosidase (GCase), the lysosomal storage enzyme lacking in Gaucher's, appears to be an early step in the degeneration of dopaminergic neurons that underlies Parkinson's disease, said , of Northwestern University in Chicago.
Moreover, research in his lab shows that this is a small-molecule druggable target, he told attendees here at the American Academy of Neurology annual meeting.
Gaucher's "is clinically and genetically linked to Parkinson's," Krainc explained in a "Hot Topics" plenary lecture. Among the connections:
- Patients with Gaucher's disease and asymptomatic carriers of the associated GCase genetic mutation are at increased risk to develop Parkinson's
- Lewy bodies, an intraneuronal feature of Parkinson's, are also seen in Gaucher patients
- GCase mutations are seen at increased rates in Parkinson patients
- Carriers of such mutations are at high risk for Lewy body dementia
Collectively, these links suggest that both conditions share a pathway related to alpha-synuclein protein, Krainc said.
Previously published data from his lab showed that mutated GCase leads to accumulation of both soluble and insoluble alpha-synuclein within the lysosome -- a structure within mammalian cells that serves a variety of housekeeping functions including digestion of unneeded proteins.
There is also an interaction in the other direction: increased levels of alpha-synuclein interferes with GCase activity.
Recent studies in Krainc's lab submitted for publication indicate that oxidized dopamine modifies GCase in such a way as to diminish its enzymatic activity.
These findings point to GCase activity as a modifiable factor. His lab has now set out to identify small-molecule drugs that increase GCase activity -- not just mutated versions but also the normal enzyme. If the model Krainc described is accurate, such agents should improve lysosomal function and decrease accumulation of alpha-synuclein -- and hence interrupt the process leading to Parkinson's disease.
Last year, experiments with one such agent, dubbed simply compound 758, were .
Krainc said that boosting GCase activity has an important advantage as a drug target over other approaches to Parkinson's: the enzyme is present in blood and in cerebrospinal fluid. As a result, whether a drug is "engaging" the target is readily measurable with minimally invasive tests. That in turn allows researchers to determine early on whether a particular agent is worth more extensive and expensive development.
The "holy grail" of Parkinson's disease therapeutics would be an agent that can be given to patients identified as at increased risk for the condition before symptoms develop, Krainc noted. By the time tremors and gait abnormalities appear, degeneration in the substantia nigra is already far advanced; stabilization at that point is the most that could be hoped for.
Better, he said, would be to prevent the degeneration in the first place.
One seemingly obvious alternative approach suggested by the Gaucher's disease link probably can't work, Krainc added. Gaucher patients are currently treated with GCase replacement products, so one might think that simply giving these could be effective against Parkinson's too.
But he pointed out that these products only restore 20%-30% of normal GCase activity in Gaucher patients. That is enough to alleviate their symptoms, but it would be unlikely to be enough to stave off Parkinson's in at-risk patients.
Disclosures
Krainc disclosed being a founder of , which seeks to commercialize his work, and a relevant relationship with Intellia Therapeutics.
Primary Source
American Academy of Neurology
Krainc D "Lysosomal Proteins as a Therapeutic Target in Neurodegeneration" AAN 2017.