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Finland is known for its snowy landscapes and herds of reindeer.
In 2014, Finland became famous for a very different reason: researchers discovered Finnish people carrying a new type of mutation – known as A53E – in the SNCA gene that causes Parkinson disease (PD).
PD is a neurodegenerative disease characterized by progressive problems with movement. Many people with PD will also experience impaired mental function. Some hereditary forms of the disease are caused by mutations in the SNCA gene and may develop at a younger age than non-hereditary forms.
To date, at least six different SNCA mutations have been detected in PD patients.
Until recently, the A53E mutation had only been found in Finnish families with PD.
But Dr. Lorraine Kalia, a neurologist and Scientist at the Krembil Research Institute, has reported the discovery of a Canadian family with PD caused by the A53E mutation. This work was done in collaboration with colleagues at the Krembil, the Morton and Gloria Shulman Movement Disorders Clinic and Edmond J. Safra Program in Parkinson's Disease at Toronto Western Hospital, and the Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto.
Using genetic tests and the family's medical history, Dr. Kalia and her colleagues found that the A53E mutation is likely to have occurred spontaneously and was not inherited from a Finnish ancestor. The tests also suggest that the pattern of methyl molecules "decorating" the patients' DNA might contribute to the earlier appearance of symptoms in PD patients with SNCA mutations.
Given that the SNCA gene provides the instructions for making the protein α-synuclein, Dr. Kalia and her colleagues also examined the effect of the A53E mutation on the protein's behaviour in test tubes and in cells.
They showed that the mutated proteins had an increased tendency to form "clumps" and that attaching a phosphoryl molecule onto the proteins caused them to assemble into "fibres." Similar clumps and fibres of α-synuclein are typically found in the brains of PD patients and are believed to be toxic to brain cells and thus are key contributors to neurodegeneration.
"They show that the A53E mutation should not be ruled out as a cause of Parkinsonism outside of Finland," Dr. Kalia says of the findings. "They also provide new insights into the mechanisms underpinning Parkinson disease, as well as other neurological diseases involving α-synuclein."
This work was supported by the Canadian Institutes of Health Research, the Canadian Consortium on Neurodegeneration in Aging, and the Toronto General & Western Hospital Foundation (TGWHF).