The hallmark Alzheimer’s disease protein tau requires a specific “sulfate code” to enter cells and alter normal proteins, according to a new study. Also, the identification of enzymes involved in the cellular uptake of corrupted proteins could lead to new therapies for neurodegenerative diseases, researchers say.
The research, “Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus α-synuclein and β-amyloid aggregates,” was published in The Journal of Biological Chemistry.
Both Alzheimer’s and Parkinson’s are characterized by the formation of protein clumps in the brain. In Alzheimer’s, plaques mainly composed of misfolded beta-amyloid proteins form outside the cells, while a modified form (called hyperphosphorylated) of the protein tau forms intracellular tangles. In turn, patients with Parkinson’s typically exhibit Lewy bodies primarily composed of a protein known as alpha-synuclein.
These protein aggregates induce normal proteins to also misfold and clump together. Cell-to-cell propagation of aggregate “seeds” is regarded as a key mediator of progression of neurodegenerative diseases.
Scientists from UT Southwestern Medical Center, in Dallas, Texas, previously reported that, to enter cells and form new aggregates, the disease-associated proteins tau and alpha-synuclein bind to heparan sulfate proteoglycan (HSPG), a sugar-protein molecule located on the cell surface.
HSPGs can have different sizes and structures. They also may have different patterns of sugar molecules, which can, in turn, contain different compositions of sulfur-containing groups called sulfate moieties.
Now, aiming to explore the precise binding mechanisms to HSPGs, scientists first assessed the impact of different lengths and patterns of sulfate moieties in the binding of alpha-synuclein, amyloid-beta, and tau to long sugar molecules called glycosaminoglycans (GAGs).
They found that misfolded tau required a specific composition of sulfate moieties for cellular entry, while beta-amyloid and alpha-synuclein were more flexible. “Our results indicate considerable specificity for tau aggregate interaction with HSPGs,” the investigators wrote.
The team then sought to identify the enzymes required for aggregate uptake. They discovered that genetic removal of the enzymes exostosin 1, exostosin 2, exostosin-like 3, and N-sulfotransferase significantly reduced the entry of both tau and alpha-synuclein in cells, while 6-O-sulfotransferase was involved in the uptake of tau only.
The scientists hypothesized that deleting these enzymes changed the HSPG sugar composition and its sulfate patterns; consequently, tau no longer recognized the “molecular password” to enter cells.
The team now plans to study if these mechanisms found in cell culture also are observed in the brain, ultimately hoping that understanding how altered proteins migrate between brain cells will lead to strategies to halt degeneration.
“There’s something very remarkable about how efficiently a cell will take up these aggregates, bring them inside and use them to make more,” Marc I. Diamond, the study’s senior author, said in a press release.
“This knowledge has important implications for our understanding how neurodegenerative diseases get worse over time. Because we have identified specific enzymes that can be inhibited to block this process, this could lead to new therapies,” Diamond concluded.