Mutation in one Parkinson’s protein eases cellular traffic jams caused by another

BUFFALO, N.Y. — A hallmark of Parkinson’s disease is the buildup of Lewy bodies — misfolded clumps of the protein known as alpha-synuclein.

Long before Lewy bodies form, alpha-synuclein can interfere with neurons’ ability to transport proteins and other cargo along their axons to the synapses. When present at high levels, alpha-synuclein binds too tightly to structures inside the axon, creating the cellular equivalent of traffic jams. These disruptions may even help set the stage for the later accumulation of Lewy bodies in the brain.

Now, University at Buffalo researchers have identified a way to reduce these traffic jams and restore flow — by altering how alpha-synuclein interacts with another Parkinson’s-related protein known as leucine-rich repeat kinase 2 (LRRK2).

In a study published last month in Frontiers, the researchers increased levels of specific mutant forms of LRRK2 in fruit fly larvae. They found that one mutation had a downstream effect on alpha-synuclein, limiting its ability to bind to cargo and disrupt axonal transport.

“This finding suggests that alpha-synuclein and LRRK2 proteins must act together — and be in the right balance — for axonal transport to be disrupted,” says the study’s corresponding author, Shermali Gunawardena, PhD, associate professor of biological sciences in the UB College of Arts and Sciences. 

These LRRK2 mutations, which are seen in Parkinson’s patients, altered sections of the protein that regulate its enzymatic activity and its ability to interact with other proteins via its WD40 domain. The mutations in and of itself did not affect cargo trafficking, but excess of the mutation in the WD40 domain eased alpha-synuclein traffic jams.

“A mutation doesn’t necessarily kill a protein’s function. It can exaggerate it, suppress it, or lead to an entirely new function,” Gunawardena says. “It can be complicated to untangle, but in this case the results suggest the WD40 mutation can suppress LRRK2’s ability to interact with alpha-synuclein, perhaps within membranes.”

However, the LRRK2 mutations and subsequent improved axonal transport did not have any effect on neuronal cell death. It’s also unclear whether they have any effect on later Lewy body formation,

The study’s most significant implication, the researchers say, is establishing a functional link between two of the genes known to cause familial Parkinson’s disease. The SNCA gene, which produces alpha-synuclein, and the LRRK2 gene, which produces the LRRK2 protein, are two of eight genes in which inherited mutations can significantly increase Parkinson’s risk.

“These eight Parkinson's-related genes all appear to have different functions, which has made it difficult to understand what actually triggers Parkinson’s at the earliest stages,” Gunawardena says. “By finding a functional link between two of them, we’re providing a somewhat clearer picture of how this disease can start.”

Other authors on the study include current and former UB students Piyali Chakraborty, Pratima Bajgain, Jing Huang, Rakibul Islam and Rupkatha Banerjee. 

The work was supported by the BrightFocus Foundation and the National Institutes of Health.