The cause of neurodegenerative disorders takes shape

Several neurodegenerative disorders are caused by aggregates of a single protein known as alpha-synuclein, though no-one exactly knows why. Neurobiologists from CNRS, the University of Antwerp and KU Leuven have now discovered that the shape of these aggregates - ‘cylinders’ or ‘ribbons’ - determines whether a patient develops Parkinson’s disease or multiple system atrophy (MSA), respectively.

The exact function of alpha-synuclein in the nervous system remains unclear, though it may play an important role in synapses. The protein also forms aggregates in the brain, which lead to neurodegenerative disease such as Parkinson’s disease, MSA or dementia with Lewy bodies (DLB).

“When alpha-synuclein aggregates accumulate within a brain cell, they interfere with the normal functioning of the cell,” said Professor Veerle Baekelandt from KU Leuven’s Research Group for Neurobiology and Gene Therapy. “The protein aggregates disrupt the communication between brain cells, resulting in cell death. Up to now, nobody understood how aggregates of this single protein could induce different pathologies.”

Writing in the journal Nature, the research team has demonstrated how a single protein can cause different diseases that do not affect the same cerebral functions. It all began in 2013, when CNRS Professor Ronald Melki and his colleagues isolated several forms of alpha-synuclein fibres called ‘strains’.

“The two most important strains were cylinder-shaped fibres reminiscent of spaghetti and broad ribbons that resemble linguini,” said KU Leuven doctoral researcher Wouter Peelaerts. “We injected these fibres separately into the brain and bloodstream of rats.”

The fibres proved to be toxic to neurons and recruited the endogenous alpha-synuclein of the rats, causing the formation of further aggregates. The scientists already knew that the fibres acted like prions, but they were also able to observe that these aggregates moved along the axons of neurons.

“We noticed that the rats developed different symptoms: while the ‘cylinders’ induced Parkinson’s disease, the ‘ribbons’ caused MSA symptoms,” said Peelaerts.

This demonstrates that distinct diseases result from alpha-synuclein fibres that are structurally different. And Professor Baekelandt believes that more fibres with different shapes and effects are “waiting to be discovered”.

“In any case, our findings open up possibilities for the development of new treatments,” Professor Baekelandt said. “A drug that counteracts the development of aggregates could be used to treat a whole range of brain diseases.”