Small amounts of a particular form of alpha-synuclein, known as beta-sheet, may cause a significant loss of dopamine-releasing neurons by recruiting more alpha-synuclein molecules, leading to Parkinson’s-like symptoms and disease progression, according to a recent lab study.
The study, “Defining α-synuclein species responsible for Parkinson disease phenotypes in mice,” was published in the Journal of Biological Chemistry.
In Parkinson’s, a particular form of the protein alpha-synuclein originates in insoluble fibrils (i.e. “small fibers”) that clump together, and those fibers accumulate inside nerve cells (neurons). These aggregates, also known as Lewy bodies, are harmful to cells and eventually kill them, which, in turn, contributes to the onset of disease-related symptoms.
Besides fibrils, alpha-synuclein exists in other structural forms, including an orderly stacked form called beta-sheet. To date, not much is known about which of alpha-synuclein’s structural arrangements contribute more strongly to disease mechanisms and Parkinson’s manifestations.
Researchers at the University of Alabama at Birmingham (UAB) studied three distinct structural forms of alpha-synuclein (long fibrils, a mix of fragmented fibrils, and short fragmented fibrils; all with beta-sheet in them) to determine which was most responsible for Parkinson’s-related damage.
Investigators injected one of the three alpha-synuclein forms, as well as small (insoluble) alpha-synuclein fibers, into the striatum — a crucial brain region involved in motor control that’s extensively damaged in Parkinson’s — of healthy mice to establish the ability of each protein arrangement to induce Parkinson’s-like symptoms.
Three months after injection of small alpha-synuclein molecules (that have a lesser amount of beta-sheet in them) there was a slight but significant loss of dopamine-producing neurons in the substantia nigra – a brain area deeply connected with the striatum. But it did not induce Lewy body formation or lead to evidence of motor impairment.
In contrast, those animals injected with short beta-sheet fibril fragments showed fewer striatal dopamine terminals (meaning “neuronal sites where dopamine is released to communicate with nearby neurons”), a loss of dopaminergic neurons within the substantia nigra, and Parkinson’s-like motor behavior defects.
“Our findings indicate that the form most toxic to neurons was a structure referred to as beta-sheet fibrillar fragments,” Laura Volpicelli-Daley, PhD, assistant professor at UAB’s Department of Neurology, and the study’s lead author, said in a press release.
“This is a form of alpha-synuclein that makes overlapping sheets of the protein, which subsequently develop into long filaments. The filaments can then break into smaller fragmented pieces. We hypothesize that the smaller fibrillar fragments are the most toxic to neurons because they are able to attract and corrupt normal alpha-synuclein, causing it to form aggregates that spread throughout the neuron, causing damage to the brain,” Volpicelli-Daley added.
“Our results suggest that inhibiting the accumulation of small fibrillar [alpha]-synuclein fragments generated either during the process of protein aggregation or by the fragmentation or disaggregation of longer fibrils, have the potential to be a therapeutic strategy against [Parkinson’s disease] progression,” the researchers concluded.
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