The research, “Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies,” was published in the journal Nature.
Aggregates of the protein alpha-synuclein are characteristic of Parkinson’s, Lewy body dementia, and nearly 50 percent of Alzheimer’s cases. These clumps form inside neurons as Lewy bodies (LBs) and Lewy neurites in neuronal projections such as nerve fibers.
However, in multiple system atrophy (MSA), a progressive neurodegenerative disorder that affects movement and involuntary processes such as blood pressure and digestion, alpha-synuclein behaves differently and builds-up mainly outside the nucleus as glial cytoplasmic inclusions (GCIs) in oligodendrocytes — glial cells that form the protective layer of nerve fibers called myelin.
“Years ago we found that [alpha-synuclein] fibrils (aggregates) act as ‘seeds’ that induce normal [alpha-synuclein] protein to aggregate into clumps,” Virginia M.-Y. Lee, PhD, the study’s senior author, said in a press release. Her team also had shown that alpha-synuclein aggregates are taken up by healthy neurons, impairing cell function and causing neuronal death.
The team at the Perelman School of Medicine at the University of Pennsylvania found that the shape and biology of alpha-synuclein is different in GCIs versus LBs. Using animal models, researchers observed that GCIs were more compact and had a nearly 1,000-fold greater potency in seeding and spreading, which matches the highly aggressive nature of MSA, researchers observed.
“These unexpected findings of the effect of cell type on the generation of different [alpha-synuclein] strains addresses one of the most important mysteries in neurodegenerative disease research,” said study lead author Chao Peng, PhD.
Additional experiments in cells and mouse models revealed that human brain-derived alpha-synuclein from GCIs and LBs did not show a preference for a specific cell type when inducing aggregates.
“Thus [alpha-synuclein] strains are determined by both misfolded seeds and intracellular environments,” researchers wrote.
The team will now try to find the molecular processes underlying these differences between cell strains, and believe that the molecules responsible for the more potent GCI strain may be a promising therapeutic target for MSA, and also explain why treatments for other disorders with alpha-synuclein aggregates may not work for these patients.