Researchers have found that excess levels of calcium in the brain may lead to the formation of toxic clusters, Lewy bodies, that are the hallmark of Parkinson’s disease.
The international team, led by the University of Cambridge, UK, found that calcium can mediate the interaction between small membranous structures inside nerve endings, which are important for neuronal signalling in the brain, and alpha-synuclein, the protein associated with Parkinson’s disease.
Excess levels of either calcium or alpha-synuclein may be what starts the chain reaction that leads to the death of brain cells.
The findings, reported in the journal Nature Communications, represent another step towards understanding how and why people develop Parkinson’s disease. According to the charity Parkinson’s UK, one in every 350 adults in the UK – an estimated 145,000 in all – currently has the condition, but as yet it remains incurable.
What is alpha-synuclien?
- Alpha-synuclein is a protein which is abundant in the human brain. It is also present in other body tissues, notably the heart, muscle and gut. In the brain, it tends to be concentrated near the tips of the nerve cells (neurons) in association with synaptic vesicles which are responsible for the release of chemicals between neurons – neurotransmission; and
- It is a protein whose function in the healthy brain is currently unknown. It is of great interest to Parkinson’s researchers because it is a major constituent of Lewy bodies, protein clumps that are the pathological hallmark of Parkinson’s disease.
Parkinson’s disease is one of a number of neurodegenerative diseases caused when naturally-occurring proteins fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. These amyloid deposits of aggregated alpha-synuclein are the sign of Parkinson’s disease.
Dr Gabriele Kaminski Schierle from Cambridge’s Department of Chemical Engineering and Biotechnology, said: “Alpha-synuclein 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.”
Super-resolution microscopy techniques now make it possible to look inside cells to observe the behaviour of alpha-synuclein. The researchers isolated synaptic vesicles, part of the nerve cells that store the neurotransmitters which send signals from one nerve cell to another.
In neurons, calcium plays a role in the release of neurotransmitters. The researchers observed that when calcium levels in the nerve cell increase, the alpha-synuclein binds to synaptic vesicles at multiple points, causing the vesicles to come together. This may indicate that the normal role of alpha-synuclein is to help the chemical transmission of information across nerve cells.
An imbalance can be caused by a genetic doubling of the amount of alpha-synuclein by an age-related slowing of the breakdown protein, by an increased level of calcium in neurons that are sensitive to Parkinson’s disease, or an associated lack of calcium buffering capacity in these neurons.
Understanding the role of alpha-synuclein in physiological or pathological processes may aid in the development of new treatments for Parkinson’s disease.