The presence of toxic protein deposits, or Lewy bodies, inside brain cells is a recognized hallmark of Parkinson's disease.
The deposits contain clusters of alpha-synuclein and other proteins that have folded into the wrong shape.
The new study — now published in the journal Nature Communications — shows that calcium affects the way in which alpha-synuclein binds to synaptic vesicles.
Synaptic vesicles are small compartments in nerve terminals that hold the neurotransmitters, or chemical messengers, that carry signals between brain cells.
"There is a fine balance," notes co-first author Dr. Amberley Stephens, a postdoctoral researcher in molecular neuroscience at the University of Cambridge, "of calcium and alpha-synuclein in the cell, and when there is too much of one or the other, the balance is tipped and aggregation begins, leading to Parkinson's disease."
Normal vs. abnormal alpha-synuclein
Worldwide, there are more than 10 million people living with Parkinson's disease, including around 1 million in the United States. In Parkinson's disease, there is a progressive destruction of brain cells that produce a neurotransmitter called dopamine, which is important for controlling movement.
Therefore, as the disease progresses, there will be a worsening of symptoms such as slowness of movement, rigidity, tremor, and impaired coordination and balance.
More recent studies have revealed that Parkinson's also affects brain cells that do not produce dopamine, which might explain why some of the symptoms are not movement-related.
Although abnormal clusters of alpha-synuclein — a small protein comprising only 140 amino acids — is a major element of the Lewy bodies that are present in Parkinson's disease, its normal form appears to be necessary for a number of brain cell functions.
However, apart from knowing that the protein somehow interacts with synaptic vesicles to ensure the smooth transport of molecules across the synapse — or the gap between the nerve terminal and the next cell — we know little about the underlying mechanism.
Alpha-synuclein acts 'like a calcium sensor'
"Alpha-synuclein," notes senior study author Dr. Gabriele Kaminski Schierle, of the Department of Chemical Engineering and Biotechnology at the University of Cambridge, "is a very small protein with very little structure, and it needs to interact with other proteins or structures in order to become functional, which has made it difficult to study."
Advances in microscope technology mean that researchers can now observe what happens inside cells.
Dr. Kaminski Schierle and colleagues used "super-resolution microscopy" and "isolated synaptic vesicles" to examine the detailed behavior of alpha-synuclein.
They found that when the level of calcium rises in the cell, alpha-synuclein binds to vesicles at more than one point, which causes the vesicles to cluster.
"We think," explains co-first author Dr. Janin Lautenschläger, also of the Department of Chemical Engineering and Biotechnology, "that alpha-synuclein is almost like a calcium sensor."
"In the presence of calcium," she continues, "it changes its structure and how it interacts with its environment, which is likely very important for its normal function."
A delicate balance
The authors propose that the abnormal clusters of alpha-synuclein form when the delicate balance between the protein and calcium is upset. They suggest a number of things that might cause such an imbalance, such as:
- age-related slowing of the elimination of excess protein
- doubling of alpha-synuclein production due to gene duplication
- higher calcium levels in brain cells vulnerable to Parkinson's
- inability to buffer calcium effectively in Parkinson's-sensitive cells
A more detailed understanding of how alpha-synuclein behaves in both health and disease should lead to much-needed new drugs for Parkinson's disease, the authors conclude.
They also note that a drug that blocks the calcium channel in heart disease might "prove to be a valuable candidate to act against [Parkinson's disease] via lowering intracellular calcium load."
"This is the first time we've seen that calcium influences the way alpha-synuclein interacts with synaptic vesicles."
Dr. Janin Lautenschläger