A Protein Linked to Parkinson’s Disease Can Transmit Between Brain Cells
Researchers at Yale have discovered a pair of interacting proteins that seem to assist a protein linked to Parkinson’s disease, α-synuclein, in transferring from one brain cell to another, leading to neuronal injury. The proteins, mGluR4 and NPDC1, are located on the surfaces of dopamine-producing neurons in the substantia nigra, the brain area whose degeneration results in movement issues associated with Parkinson’s. In laboratory cell studies and mouse models, both proteins interacted with and internalized fibrils of misfolded α-synuclein. The research published in Nature Communications was led by a Yale School of Medicine team, with co-first authors Azucena Perez-Canamas and Mingming Chen, along with neurologist and neuroscientist Stephen Strittmatter.
A Protein Capable of Spreading from Cell to Cell
Parkinson’s is a movement disorder characterized by tremors, rigidity, slowed movements, and balance difficulties. These symptoms are connected to the loss of dopamine-producing neurons in the substantia nigra. Within affected neurons, α-synuclein can misfold and generate abnormal structures. Evidence indicates that misfolded α-synuclein can be released and absorbed by adjacent cells, promoting further protein misfolding. This “prion-like” spread refers to a molecular process instead of an infection, as no pathogen is involved, and Parkinson’s is not contagious. A significant question is how extracellular α-synuclein fibrils connect with neurons and penetrate them.
A Survey of 4,401 Membrane Proteins
The Yale researchers screened 4,401 genes coding for membrane-associated proteins to determine if misfolded α-synuclein fibrils would bind to them. The screen revealed 16 previously unidentified binding proteins. Scientists focused on mGluR4 and NPDC1 due to their expression in nigral dopamine neurons that are susceptible in Parkinson’s. Experiments indicated both proteins can bind to and assist in internalizing α-synuclein, and that mGluR4 and NPDC1 interact to form a complex crucial to the process.
Findings from the Mouse Experiments
Researchers studied genetically altered mice across two experimental setups. In one, injected α-synuclein fibrils in the striatum caused detrimental changes to dopamine-producing neurons. Deleting Grm4, the gene for mGluR4, or Npdc1 protected many neurons. The gene knockouts did not prevent all protein accumulation but diminished the link between protein deposits and neuronal death. In another setup using mice that produce a disease-associated form of human α-synuclein, the removal of Grm4 enhanced survival and certain movement metrics. Eliminating Npdc1 did not significantly enhance survival or all behavioral assessments. Optimal results were observed when both mGluR4 and NPDC1 were decreased, improving survival and mitigating movement difficulties.
Importance of the Findings for Treatment
Most treatments for Parkinson’s address symptoms but do not halt neuron degeneration. Levodopa effectively replenishes dopamine but exhibits fluctuating advantages and can induce dyskinesia with prolonged use. Experimental methods aim to prevent α-synuclein misfolding, eliminate abnormal proteins, influence immune responses, or modify biological pathways. The Yale research focuses on the interaction enabling extracellular α-synuclein to enter neurons. mGluR4 may be a more familiar target for drug development as it is part of a well-explored family of glutamate receptors. A prior mGluR4-modifying compound reached a phase 2 trial but did not demonstrate a significant symptomatic benefit or potential to change disease progression.
Magnitude of the Issue
The Parkinson’s Foundation estimates that over 1.1 million people in the US are living with Parkinson’s, with nearly 90,000 new cases each year. Worldwide, the figure surpasses 10 million. Given that age is the most substantial risk factor, patient numbers are anticipated to increase as the population ages, underscoring the lack of a verified disease-modifying treatment.
Future Directions
The forthcoming challenge is to establish whether the mGluR4-NPDC1 interaction can be pharmacologically disrupted rather than through genetic means. Researchers will need to identify which components of the complex to target, whether a drug can access brain tissue, and the long-term effects of modifying the pathway. Human Parkinson’s is more intricate than mouse models. Many neuroprotective therapies in animals have fallen short in clinical trials, especially when treatment starts post significant damage.
A More Accurate Perspective on Parkinson’s Progression
This discovery is part of a larger effort to comprehend neurodegenerative diseases as processes involving interactions between cells rather than solely within individuals. Misfolded proteins in Alzheimer’s, Huntington’s, ALS, and Parkinson’s can migrate through tissue and stimulate further misfolding. Researchers are concentrating on the receptors, transport pathways, and extracellular interactions that facilitate this movement. mGluR4 and NPDC1 have not yet been validated as treatment targets in humans. However, identifying