Validating drug targets in mini-brains

Validating potential molecular targets for treating conditions of the human brain, like Parkinson’s disease, can be difficult. Researchers at the Garvan Institute for Medical Research in Sydney are looking to differentiate human induced pluripotent stem cells (IPSCs) into neurons to validate potential new targets.

“We have identified potential targets for treatment of Parkinson’s disease and have received funding for the target validation stage of this research,” said Associate Professor Antony Cooper from the Garvan, whose research recently received funding of $80,000 from The Michael J. Fox Foundation for Parkinson’s Research and Shake It Up Australia Foundation.

“It will be a 12-month project in the first instance,” Cooper added. “The funding from these organisations has stages in a pipeline - we now need to show that these targets occur in the human brain to be eligible for the next stage of funding.”

Cooper said the most likely way they will do this is by differentiating human IPSCs into neurons. “Other researchers have differentiated IPSCs into neurons and mini brains,” he said. “We are starting to work with IPSCs.”

The research will look at the role of long non-coding RNAs in Parkinson’s disease.

Recent genome-wide association studies comparing the DNA or single nucleotide polymorphisms (SNPs) of thousands of healthy people with those of people with Parkinson’s disease have revealed regions of the genome that differ between the two groups.

Cooper has found several long non-coding RNAs in these regions that correlate strongly with disease.

Long non-coding RNAs are complex molecules, usually >200 base pairs long that appear to play a regulatory role over chromatin structure and processes such as transcription rates and RNA stability. Unlike conventional genes and RNA, they do not encode for proteins.

“Most SNPs do not fall on protein-coding genes,” Cooper explained. “We plan to look at some of these regions of difference the genome-wide association studies identified that show disregulated expression.”

Collaborating with Professor John Mattick, an expert in long non-coding RNAs, Cooper will extract RNA from the post-mortem brains of people who had Parkinson’s disease and healthy ‘controls’.

The team will use a new technique developed by the Mattick lab called RNA CaptureSeq, which uses specific oligonucleotides to capture and study RNA of interest.

The hope of all parties is that this project leads to breakthroughs for screening and early diagnosis of Parkinson’s disease as well as new therapies for patients.

Shake It Up Australia Foundation is a not-for-profit organisation established in 2011 to promote and fund Parkinson’s disease research in Australia. The Michael J. Fox Foundation for Parkinson’s Research conducts similar work in the United States.