Alpha-synuclein in LRRK2-related Parkinson's disease
Researchers have identified a protein called alpha-synuclein as a major culprit in Parkinson’s disease because it accumulates in large clumps, known as Lewy bodies, that are associated with the death of dopamine-producing brain cells.
At the University of Toronto, Dr. Lorraine Kalia, a neurologist and neuroscientist, is investigating a different form of alpha-synuclein that behaves – or misbehaves – in another way. Autopsies on the brains of some people with a genetic form of Parkinson’s have revealed they don’t have Lewy bodies. So Kalia is trying to find out why their dopamine-producing brain cells died.
Kalia has collected autopsy cases of people with genetic Parkinson’s disease, caused a mutation in the LRRK2 gene. She believes people with that form of Parkinson’s may have smaller clumps of alpha-synuclein, called oligomers, in their brain cells.
“These smaller aggregates may be the larger culprit for what kind of alpha-synuclein causes brain cells to die,” she says.
Kalia is comparing the brains of people who did have Lewy bodies – the large aggregates of alpha-synuclein – to the brains of those who did not have those large clumps. She’s looking for the smaller oligomers.
“The protein is still building up in brain cells, but not in the same way,” she says. “It’s still there, it’s still misbehaving, but possibly in these smaller clumps.”
Once Kalia and her team have determined how large and how many oligomers there are in the brains of people with this genetic form of Parkinson’s, she’ll determine if the way the oligomers are distributed in the brain correspond to different symptoms.
Kalia’s previous research suggests people with Lewy bodies were more likely to have dementia or other non-motor symptoms than those without Lewy bodies.
She hopes this research will shed light on whether the location of the clumps of misbehaving proteins, or the type and size of clumps – Lewy bodies or oligomers – correspond to non-motor symptoms.
Ultimately, Kalia hopes her research will open a new avenue for drug testing or other forms of therapies to treat whichever form of alpha-synuclein is causing the problems.
Although 75 percent of her time is spent on research, Kalia spends the other 25 percent caring for people who have Parkinson’s.
“My exposure to people who have Parkinson’s disease is really what inspired me to pursue a career in movement disorders,” she says. “The fact that we have a lot of clinical unmet needs in Parkinson’s disease … is the driving force of the lab.”