Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, are associated with abnormally folded proteins that form clumps inside brain cells. These clumps spread from cell to cell, eventually leading to cell deaths. All three of these diseases are progressive, debilitating, and incurable.
Now a new study at Loyola University Chicago shows that although different proteins are implicated in each disease — tau in Alzheimer’s, alpha-synuclein in Parkinson’s, and huntingtin in Huntington’s disease — they all appear to cause damage to brain cells in a similar way.
The findings, published in the journal Acta Neuropathologica, show the processes by which neurodegenerative diseases may spread and disrupt normal brain functions. The study also supports the notion that one type of treatment may be effective for all three neurodegenerative diseases.
“A possible therapy would involve boosting a brain cell’s ability to degrade a clump of proteins and damaged vesicles,” said senior author Edward Campbell, Ph.D.. “If we could do this in one disease, it’s a good bet the therapy would be effective in the other two diseases.”
For the study, researchers focused on how these misfolded protein clumps invade a healthy brain cell. They found that once proteins get inside the cell, they enter vesicles (small compartments that are encased in membranes).
The proteins then damage or rupture the vesicle membranes, allowing the proteins to invade the cytoplasm and cause additional dysfunction. The cytoplasm is the part of the cell that’s outside the nucleus.
The findings also revealed how a cell responds when protein clumps invade vesicles: The cell gathers the ruptured vesicles and protein clumps together so they can all be destroyed, but the proteins are resistant to degradation.
“The cell’s attempt to degrade the proteins is somewhat like a stomach trying to digest a clump of nails,” Campbell said.
The finding that protein clumps associated with the three diseases cause the same type of vesicle damage was unexpected, said first author William Flavin, Ph.D.. Each disease affects different regions of the brain: Alzheimer’s destroys memory-related areas, while Parkinson’s and Huntington’s affect those associated with movement.
Since the researchers had initially focused on alpha-synuclein proteins associated with Parkinson’s disease, they asked collaborator Ronald Melki, Ph.D., a protein researcher at the Paris-Saclay Institute of Neuroscience, to send them samples of different types of alpha-synuclein.
To do the experiment in a blinded, unbiased manner, the Loyola researchers did not know which types of alpha-synuclein were which. Without telling the Loyola researchers, Melki sent other types of proteins as well. This led to the surprise finding that tau and huntingtin proteins also can damage vesicles.
Campbell says the study’s findings need to be followed up and confirmed in future research.
Source: Loyola University Health System