Vocal Changes May Be Caused by Alpha-synuclein Clumps: Study

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by Patricia Inácio, PhD |

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Insoluble clumps of the alpha-synuclein protein accumulating in the brain — a hallmark of Parkinson’s disease — can affect patients’ voice, with changes likely occurring years before they develop motor symptoms, a new study suggests.

The research, which used the zebra finch — a songbird native to Australia — as a model, could help detect the disease at its early stages.

The study, “Vocal changes in a zebra finch model of Parkinson’s disease characterized by alpha-synuclein overexpression in the song-dedicated anterior forebrain pathway,” was published in Plos One.

Parkinson’s disease is mostly known for its motor symptoms, particularly tremors and stiffness, but it can also result in patients displaying a soft, monotonous voice. Speech rate is also affected. Previous research has suggested that these symptoms appear earlier, likely decades before movement-related symptoms.

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The cause of these vocal-related issues, as well as the brain regions affected, remains largely unknown, however, due to a limited understanding of the neural circuitry for rodent vocalizations, the most common animal model used in Parkinson’s research.

“We have this big gap here – we don’t know how this disease impacts the brain regions for vocal production, and this is really an opportunity to intervene early and come up with better treatments,” Julie E. Miller, an assistant professor of neuroscience and of speech, language, and hearing sciences at the University of Arizona, said in a press release.

Researchers at the University of Arizona used the zebra finch to investigate how a Parkinson’s-related gene — SNCA — may impact vocal changes in the disease.

The SNCA gene is responsible for producing the protein alpha-synuclein. The accumulation of toxic clumps of misfolded alpha-synuclein inside dopamine-producing nerve cells — those responsible for releasing dopamine — trigger their death. A neurotransmitter, dopamine is a chemical messenger essential for muscle control and its loss is a hallmark of Parkinson’s.

Birds are an ideal model to study speech and the mechanisms regulating voice. Young finches learn their songs from older, father-like male birds and the brain regions that regulate language and speech are organized similarly to that of human brains.

“These similarities across behavior, anatomy and genetics allow us to use the zebra finches as a model for human speech and voice,” César A. Medina, PhD, the study’s lead author, said.

To start, the researchers recorded male birds singing to generate a baseline before any manipulation. Then they repeated the recording after a number of birds were injected with a virus carrying a normal (wild-type) version of the human SNCA gene. Birds injected with a virus that had a fluorescent protein called GFP instead of the SNCA gene were used as controls.

The gene was delivered to a brain region called Area X, which has similar functions as the basal ganglia in humans. The basal ganglia helps regulate voluntary movements. Its impact on vocal control has not been established, however.

They then recorded all the birds’ songs immediately after the gene was injected and then again one, two and three months later.

Using computer software, the team analyzed and compared the pitch, amplitude and duration of the songs between the birds over time.

The results showed that, after two months, the birds expressing the human alpha-synuclein sang less compared to control birds. At three months after receiving the gene, they sang less at the start of a song session, the first 30 minutes.

Their vocalizations were also softer and shorter, which seemed to mimic that of Parkinson’s in people.

Moreover, analyses showed the birds’ Area X had a toxic buildup of insoluble human alpha-synuclein, supporting the link between its accumulation with changes in vocal production, Medina noted.

This is the first time that data support a connection that had been predicted in previous studies, he said.

The next step is how to apply these findings to humans, Miller said. The findings could help speed up a Parkinson’s diagnosis, before patients develop movement-related symptoms.

Miller hopes to establish partnerships with other researchers and private companies to develop new therapies that target the SNCA gene, and other genes linked with Parkinson’s.

Medina said doing this “could stop the progression of Parkinson’s disease before it becomes a detrimental impediment to the quality of life for the patient.”