Lighting up Parkinson’s disease research

Most people do not think of jellyfish at the mention of Parkinson’s disease research. But, at the MassGeneral Institute for Neurodegenerative Disease (MIND), researchers Pamela McLean and Bradley Hyman are using the same fluorescent protein that causes the green glow of
jellyfish for their experiments testing potential drugs for the
treatment of Parkinson’s disease (PD).

“Looking at the
protein alpha-synuclein, we are investigating possible strategies to
prevent or stall Parkinson’s disease by using fluorescent proteins,”
says McLean. “When alpha-synuclein protein misfolds, it easily sticks
to other protein molecules and creates clumps that are toxic to brain
cells.”

McLean and her group are using the fluorescent
protein by splitting it in half and attaching one half to the end of
one alpha-synuclein molecule and the other half to the end of a second
alpha-synuclein molecule. When two separate alpha-synuclein proteins
misfold and interact, the ends come together resulting in small clumps
that glow. Using this technology, McLean has developed experiments to
measure these errors and their toxicity to brain cells.

Closely
examining the misfolding, McLean has shown one natural way that
misfolding damage can be prevented. When the brain activates
“chaperone” proteins, these proteins can refold alpha-synuclein
correctly or transport it to the cell’s own recycling plant, where
damaged cells survive or are appropriately discarded. “Imagine a
chaperone at a dance separating two clingy teenagers, and you will have
a vivid image of the brain’s chaperone defense,” says McLean. “We are
researching whether drugs might activate additional chaperone proteins
as a way to protect the brain against the ravages of alpha-synuclein
and their resulting diseases.”

McLean is now screening a set
of drug compounds that are known to increase chaperone proteins. By
treating PD cells with drugs, she hopes to show that increasing
chaperones saves brain cells. In these experiments, cells which are not
treated with drugs will glow as the alpha-synuclein molecules bind
together, meanwhile those treated with effective compounds will remain
dark, indicating they are healthy.