Single gene manipulation eliminates Parkinson’s disease in mice

Researchers from the University of California have discovered that inhibition of the PTB gene in mice converts neural support cells into dopamine-producing neurones.

Polypyrimidine tract-binding (PTB) protein, encoded by the PTB gene, is responsible in determining which genes are switched on and off in a cell. It binds to RNA in the nucleus to influence its processing, metabolism and transport.

Researchers from the University of California San Diego School of Medicine have been studying PTB for decades; altering its level of expression to see what effect this has on RNA. The scientists decided to ditch their usual technique and created a fibroblast cell line which is permanently lacking PTB. Fibroblasts are connective tissue cells which are often used for genetic manipulation.

To the scientists’ surprise, after a couple of weeks the majority of the fibroblasts in the petri dish had been replaced by neurones.

Researchers around the world have been trying many different ways to generate neurones in the lab, for example through the use of stem cells, in order to study their development and function, as well as for use in therapy to replace lost neurones in neurodegenerative diseases. The scientists from California were able to transform fibroblasts, as well as other cell types, directly into neurones through the deletion of a single gene – that which encodes the PTB protein.

The team recently applied their findings to identify the therapeutic potential of this approach in the treatment of Parkinson’s disease and other neurodegenerative diseases. In Parkinson’s disease, the neurones which produce the neurotransmitter dopamine in the midbrain die. The team chemically poisoned dopamine neurones in mice, which induced symptoms of Parkinson’s disease. They then developed a non-infectious virus which served as a vector to introduce an antisense oligonucleotide sequence – a piece of DNA designed in the lab to specifically bind the RNA coding for PTB – into cells and degrade the gene, thus preventing the production of the PTB protein.

The study, published in Nature, showed that a single treatment to inhibit PTB in these mice was able to convert 30% of astrocytes (brain support cells) into neurones which produced dopamine.

Dopamine is a neurotransmitter which is lacking in patients with Parkinson’s disease. It is critical to certain central nervous system functions including movement, attention and mood. Hence, sufferers of Parkinson’s disease experience tremor, a drastic change in mood, and a plethora of other symptoms accounted for by the lack of dopamine.

The increase in dopamine-producing neurones eliminated Parkinson’s disease symptoms in the mice. This exciting discovery hints at the prospect of a new treatment for Parkinson’s disease, as antisense oligonucleotides have been used in the treatment of several other neurodegenerative and neuromuscular diseases including spinal muscular atrophy.

The use of these so-called “designer DNA drugs” may be applied in the treatment of Parkinson’s disease in the future if the results in humans reflect the exciting discovery seen in mice.


Hao Qian, Xinjiang Kang, Jing Hu, Dongyang Zhang, Zhengyu Liang, Fan Meng, Xuan Zhang, Yuanchao Xue, Roy Maimon, Steven F. Dowdy, Neal K. Devaraj, Zhuan Zhou, William C. Mobley, Don W. Cleveland, Xiang-Dong Fu. Reversing a model of Parkinson’s disease with in situ converted nigral neuronsNature, 2020; 582 (7813): 550 DOI: 10.1038/s41586-020-2388-4

You may also like...