Managing misfolded proteins to prevent Parkinson's disease
The protein alpha-synuclein is abundant in healthy brains and plays an important role in enabling communication between nerve cells. However, under certain conditions, misfolded alpha-synuclein proteins can accumulate into toxic clumps inside neurons. Known as Lewy bodies, these clusters of proteins are a hallmark of Parkinson's disease and some forms of dementia.
Misfolded alpha-synuclein proteins, responsible for Parkinson's disease, can form toxic clusters called Lewy bodies in neurons. These misfolded proteins do not remain stationary; instead, they spread from one neuron to another through the fluid spaces of the brain. Stephen Strittmatter, a leading researcher, aims to uncover what happens to alpha-synuclein between nerve cells and the balance between removing it from the brain versus allowing it to spread.
To achieve this, researchers will focus on proteins that attach to and pick up misfolded alpha-synuclein, with particular interest in two selectively expressed proteins in dopamine-containing neurons: metabotropic glutamate receptor 4 (mGluR4) and NPDC1. Knocking out these proteins in preclinical models prevented dopamine-related neuron death.
Meanwhile, another team led by Eric Song will investigate how lymphatic vessels clear and drain alpha-synuclein before it binds to nerve cells. By helping the lymphatic system clear faulty proteins and limiting their uptake by nearby nerve cells, the researchers hope to slow or prevent disease spread. A new preclinical model of Parkinson's disease, developed by a Yale School of Medicine team, closely mimics human disease progression and will be used to study these findings.
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