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Calcium may play a role in the development of Parkinson's disease

last modified Mar 29, 2018 03:18 PM
Calcium may play a role in the development of Parkinson's disease

A neuron with synapses marked in green, where alpha-synuclein resides.

Researchers have found that excess levels of calcium in brain cells may lead to the formation of toxic clusters that are the hallmark of Parkinson’s disease.

The international team, led by the University of Cambridge, 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.

The findings, reported in the journal Nature Communications, represent another step towards understanding how and why people develop Parkinson’s.

The work has also been featured in a Naked Scientist podcast: Build up of Calcium could lead to Parkinson's. Dr Gabi Kaminski Schierle was interviewed as part of the show What The Heck Is Xenobiology?

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.

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, also known as Lewy bodies, are the sign of Parkinson’s disease.

Curiously, it hasn’t been clear until now what alpha-synuclein actually does in the cell: why it’s there and what it’s meant to do. It is implicated in various processes, such as the smooth flow of chemical signals in the brain, and the movement of molecules in and out of nerve endings, but exactly how it behaves is unclear.

"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," said senior author Dr Gabriele Kaminski Schierle from Cambridge’s Department of Chemical Engineering and Biotechnology.

Thanks to super-resolution microscopy techniques, it is now possible to look inside cells to observe the behaviour of alpha-synuclein. To do so, Kaminski Schierle and her colleagues isolated synaptic vesicles, part of the nerve cells that store the neurotransmitters which send signals from one nerve cell to another.

The researchers observed that when calcium levels in the nerve cell increase, such as upon neuronal signalling, the alpha-synuclein binds to synaptic vesicles at multiple points causing the vesicles to come together, which may indicate that its normal role is to help the chemical transmission of information across nerve cells.

"This is the first time we’ve seen that calcium influences the way alpha-synuclein interacts with synaptic vesicles," said Dr Janin Lautenschlӓger, the paper’s first author. "We think that alpha-synuclein is almost like a calcium sensor. In the presence of calcium, it changes its structure and how it interacts with its environment, which is likely very important for its normal function."

They further show that an imbalance of either calcium or alpha-synuclein may be what starts the chain reaction that leads to the death of brain cells. "There is a fine balance 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," said co-first author Dr Amberley Stephens.

This can be caused by a genetic doubling of the amount of alpha-synuclein (gene duplication), by an age-related slow-down in the break-down of excess protein or by an increased level of calcium in PD-sensitive neurons and a concomitant 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. One possibility is that drug candidates developed to block calcium, for use in heart disease for instance, might also have potential against Parkinson’s disease.

The research was funded in part by the Wellcome Trust, the UK Medical Research Council, Alzheimer’s Research UK, and the UK Engineering and Physical Sciences Research Council.

 

Janin Lautenschlӓger, Amberley D. Stephens et al. ‘C-terminal calcium binding of Alpha-synuclein modulates synaptic vesicle interaction.’ Nature Communications (2018). DOI: 10.1038/s41467-018-03111-4

The full list of authors is Janin Lautenschläger, Amberley D. Stephens, Giuliana Fusco, Florian Ströhl, Nathan Curry, Maria Zacharopoulou, Claire H. Michel, Romain Laine, Nadezhda Nespovitaya, Marcus Fantham, Dorothea Pinotsi, Wagner Zago, Paul Fraser, Anurag Tandon, Peter St George-Hyslop, Eric Rees, Jonathan J. Phillips, Alfonso De Simone, Clemens F. Kaminski & Gabriele S. Kaminski Schierle.

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