Alpha-synuclein Clumping Seen to Affect Mitochondria Early
Parkinson's study finds toxic protein drawn to membrane of cells' energy source
Alpha-synuclein aggregation — the toxic clumping of proteins in nerve cells that is a hallmark of Parkinson’s disease — starts on the membranes of mitochondria, the so-called powerhouse of a cell, according to work in cell models.
“Our study provides insights into what is happening in the earliest stages when proteins start to misfold, and how they affect the health of the cell,” Sonia Gandhi, PhD, a neuroscientist and professor at University College London and the study’s lead author, said in a university press release. “This provides an important piece of the puzzle in understanding the biological mechanisms driving Parkinson’s.”
The study, “Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity,” was published in Nature Neuroscience.
Toxic alpha-synuclein drawn to mitochondria in vicious cycle
Parkinson’s is marked by the oligomerization, or clumping, of the alpha-synuclein protein inside of nerve cells. These toxic clumps are thought to be a major driver of the disease, but how they form — especially in the earliest stages — has not been clear.
“There has been huge progress in understanding protein misfolding, but the major challenge has been to study the first stages of this process inside the human cell,” Gandhi said.
Researchers at London College and other U.K. institutes conducted a series of cell experiments using a technique called Förster resonance energy transfer, or FRET.
Basically, the scientists created alpha-synuclein proteins with two different fluorescent “tags” attached. Each of these tags would “glow” in response to a specific color (wavelength) of light, delivered via a laser. The glow induced by a laser from one tag can trigger a secondary glow from the other, but only if the two tags are very close to each other — i.e., if the two alpha-synuclein proteins with tags attached are clumped together.
“It’s fantastic that we have been able to use a range of state-of-the-art biophysical techniques to study how proteins misfold and cause damage in extremely complex biological samples. Our findings shed light on the very earliest events in Parkinson’s,” said Matthew Horrocks, PhD, a study co-author at the University of Edinburgh.
Using this system, the researchers tracked the dynamics of alpha-synuclein protein clumping over time. Experiments included both wild-type or unaffected alpha-synuclein, as well as cells with a Parkinson’s-associated mutation on the SCNA gene that provides instructions for making this protein.
“Our study used neurons derived from cells taken from people with Parkinson’s, meaning the neurons we worked with had the same genetic make-up and characteristics as diseased cells in patients. This means we can be more confident that our work reflects what is happening in neurons in the body,” said Minee Choi, PhD, a researcher at the Francis Crick Institute and the study’s first author.
Results of these experiments showed that alpha-synuclein aggregation occurred preferentially at membranes inside the cell, particularly mitochondrial membranes. Mitochondria are cell structures critical for energy generation, among many other functions.
Further experiments showed that cardiolipin, a fatty molecule that is a major component of mitochondrial membranes, could promote alpha-synuclein aggregation.
Protein clumping at the mitochondrial membrane was seen to impair the mitochondria’s ability to generate energy, and to spur the production of toxic molecules called reactive oxygen species (ROS). The presence of ROS further promoted alpha-synuclein aggregation, driving more mitochondrial damage and ROS in a vicious cycle that ultimately caused neuronal or nerve cell death.
“Inside cells, the effect of mROS [mitochondrial ROS] is bi-directional and self-amplifying: mROS promotes oligomerization of [alpha-synuclein] and oligomer formation impairs [mitochondrial] function and induces further mROS generation, driving the aggregation reaction,” the researchers concluded.
“We have known for some time that the mitochondria are abnormal in Parkinson’s, but it has not been clear why. This work connects where proteins misfold with how they induce mitochondrial damage, and cause cell death,” said Andrey Abramov, PhD, a study co-author and also a professor with University College London’s Institute of Neurology.
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