Progress and Prospects in Parkinson's Research/Therapy/Gene Therapy/RNA interference

Controlling gene expression by RNAi
DNA is the key information carrying molecule in all living things. It contains instructions to build and keep alive biological organisms. DNA “expresses” discrete units of information (called genes) by copying them into RNA (“transcription”) and RNA forms the template on which amino acids are arranged to form proteins (“translation”). Proteins are essential as structural components of cells and carry out all of the functions within cells.

The level at which genes are expressed and the amount of protein produced is carefully controlled; e.g. initiation of transcription, amount of RNA, initiation of translation, amount of protein generated.

RNA interference (RNAi) is a mechanism the cell uses to control the amount of RNA after it has been transcribed. RNA consists of a long string of subunits corresponding to the sequence of subunits in DNA (U replaces T in RNA). For example:

A T  T  T  C  G  T  T  A  G  G  C  C  C  A  T                   DNA

U A  A A  G  C  A  A  U  C  C  G  G  G  U  A                   RNA transcript

RNAi is induced by expression of a special class of genes in DNA called micro RNA (miRNA). These genes consist of short strings of subunits designed to bind to specific RNA transcripts:

U A  A  A  G  C  A  A  U  C  C  G  G  G  U  A                  RNA transcript

C G  U  U  A                                                miRNA

Once the miRNA binds to its target the cell destroys the RNA transcript, thus reducing (or “knocking down”) the amount of RNA and consequently reducing the level of protein generated by the target transcript.

The mechanism of RNAi that occurs naturally in cells can be exploited to knock down any gene you like; all you need is to get a short bit of RNA into the cell that will bind to the target transcript of choice.

RNAi and α-synuclein
Dominant mutations in α-synuclein have been identified in Parkinson’s sufferers. This means, out of the two copies of each gene we inherit, only one mutated copy of α-synuclein is needed to cause disease. Further, in mutant individuals approximately 50% of α-synuclein RNA transcripts will be mutant and 50% will be normal.

Sibley and Wood successfully implemented an RNAi strategy in cells that selectively reduced the level of mutant α-synuclein RNA; thus making it at least possible to use RNAi as treatment for Parkinson’s.

Using RNAi as a treatment for Parkinson’s
The major stumbling block of using RNAi to treat disease is getting the RNA to where it is needed. In neurological disease there is a problem with lack of access to the brain through the blood-brain barrier. Therefore, the RNA has to be applied directly to the area of the brain affected, which involves brain surgery.

In addition, RNAi has a limited period of effectiveness (2-3 weeks) so for chronic conditions such as Parkinson’s repeated doses would be needed.

Despite these impediments, a proof of principle experiment in primates with Parkinson’s demonstrated knock down of α-synuclein in the substantia nigra. Unless the problem of efficient and effective delivery of miRNA is solved similar treatment in humans is unlikely to become routine.

Related Pages
See also the Inheritance as Causes pages:

See also the article in the Magazine Section - RNAi and Parkinson's