A study published in the journal Nature Neuroscience, describes the identification of a novel molecular pathway that can constitute a therapeutic target for cognitive defects in Parkinson's disease.
The study showed that abnormal forms of Parkinson's disease (PD)-associated protein alpha-synuclein interact with the prion protein (PrP), triggering a cascade of events that culminates in neuronal dysfunction, causing cognitive defects that are reminiscent of those in PD.
"This is the follow up of a previous study initiated in my laboratory, where we found that particular forms of the protein alpha-synuclein cause dysfunction of neuronal circuits involved in memory formation. We did not know how this was happening, and in this new study we have detailed the molecular mechanisms involved, which suggests we now have new targets for therapeutic intervention" - explains the senior author.
Using pharmacology and genetics, the team has now defined a series of molecular events that explains the memory defects observed in animals that model some important aspects of PD.
Alpha-synuclein interaction with the prion protein (PrP) induced the phosphorylation of Fyn kinase via metabotropic glutamate receptors 5 (mGluR5). Alpha-synuclein engagement of PrPC and Fyn activated NMDA receptor (NMDAR) and altered calcium homeostasis.
Blockade of mGluR5-evoked phosphorylation of NMDAR in alpha-synuclein transgenic mice rescued synaptic and cognitive deficits, supporting the hypothesis that a receptor-mediated mechanism, independent of pore formation and membrane leakage, is sufficient to trigger early synaptic damage induced by extracellular aSyn.
Senior author adds: "We used a mouse model of PD in which human alpha-synuclein is produced and found that by blocking this interaction with PrP using a caffeine analogue, reverted the abnormal neuronal activity and memory deficits. This study links nicely with our previous work on Alzheimer's disease, further suggesting that molecules like caffeine may indeed have potential benefits against memory deficits upon neurodegeneration".
Novel protein interactions explain memory deficits in Parkinson's disease
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