Blocking Translation of α-synuclein RNA to Treat Parkinson's Disease

Parkinson's disease is a synucleinopathy, meaning that its pathology, the damage done to the brain, is driven at least in part by the aggregation of α-synuclein. Effective means to clear out α-synuclein and other protein aggregates from the aging brain, such as those resulting from amyloid-β and tau, are likely to form the basis of the first truly effective treatments for a range of neurodegenerative conditions. Though, as the Alzheimer's research community has demonstrated over the past twenty years, this is easier said than done. Little more than vast expense and failed human trials have thus far resulted from the development of immunotherapies to target the removal of amyloid-β. Success is elusive in that part of the field. Now, however, the research community is diversifying its efforts, with many groups seeking radically different approaches to the challenge of protein aggregation. Some will eventually succeed.

The exact cause of Parkinson's disease (PD) is still a mystery, but researchers believe that both genetics and the environment are likely to play a part. Importantly though, all PD patients show a loss of dopaminergic neurons in the brain and increased levels of a protein called α-synuclein, which accumulates in Lewy bodies. Lewy bodies are a pathological feature of the disease, as well as some types of dementia.

In a study published this month, researchers focused on α-synuclein as a target for a novel PD treatment. "Although there are drugs that treat the symptoms associated with PD, there is no fundamental treatment to control the onset and progression of the disease. Therefore, we looked at ways to prevent the expression of α-synuclein and effectively eliminate the physiological cause of PD."

To do this, the researchers designed short fragments of DNA that are mirror images of sections of the α-synuclein gene product. The constructs were stabilized by the addition of amido-bridging. The resulting fragments, called amido-bridged nucleic acid-modified antisense oligonucleotides (ASOs), bind to their matching mRNA sequence, preventing it from being translated into protein. After screening 50 different ASOs, the researchers settled on a 15-nucleotide sequence that decreased α-synuclein mRNA levels by 81%. "When we tested the ASO in a mouse model of PD, we found that it was delivered to the brain without the need for chemical carriers. Further testing showed that the ASO effectively decreased α-synuclein production in the mice and significantly reduced the severity of disease symptoms within 27 days of administration."



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