How CRISPR Can Cure Parkinson’s Disease
Imagine…
You’re calmly sitting when suddenly your arm begins trembling. You can stop it, but only for a short period and when you stop concentrating on controlling your arm it shakes again as if some unseen force has power over you. Over time, this shaking spreads throughout your body. Walking becomes harder and you don’t have enough control over yourself to drive or walk without assistance. With the shaking comes ailments that others can’t even see. You’re struggling to stay happy, focusing on tasks becomes harder, and your memory begins to slip. Who you are, your body, and your independence have been lost and you have no power to stop it.
What is going on?
Everything I just described is what is currently happening to my grandfather and almost 10 million other people across the globe. All those symptoms occur due to Parkinson’s Disease, a neurodegenerative disease that breaks down a person’s brain and eventually kills them with no known cure.
- Parkinsonian Tremors: Shaking that begins in the limbs and spreads to the whole body
- Depression: The brain degeneration in Parkinson’s affects dopamine-producing neurons (dopamine helps us feel happy)
- Problems with Movement: The substantia nigra is the area of the brain which controls movement and Parkinson’s decay is focused there
For years, people with Parkinson’s disease have had to live with the slow progression of the disease. The end result is inevitable and although current treatments can increase the quality of life by improving movement and treating depression, these procedures or drugs need to be used repeatedly and regularly to have any semblance of a permanent effect.
Enter CRISPR, which stands for clustered regularly interspaced short palindromic repeats. CRISPR is a gene-editing technology that promises to revolutionize treating gene-based diseases. Already, clinical trials to treat diseases like HIV, Sickle Cell Anemia, and Cystic Fibrosis are occurring with positive results. Parkinson’s Disease could soon be one of them due to a few techniques that are being researched and developed.
How does CRISPR work?
If you’ve ever used the find tool on a computer to search for a specific term in a document and then delete it or replace it you have an idea how CRISPR works. CRISPR was first discovered by researchers studying the immune system of bacteria. They found that bacteria protected themselves from phages (bacteria viruses) by saving parts of each phages’ DNA in its own genome for future reference. When the phage entered the cell again, the bacteria would transcribe a piece of guide RNA from the saved phage DNA to be used in conjunction with a CAS (CRISPR associated) protein. The protein-Guide RNA complex would find the complementary spot in the phage’s DNA and cut at that spot, destroying the phage’s DNA so it could no longer function. CAS proteins served as molecular scissors or your delete key in the find analogy. The guide RNA is analogous to whatever is typed into the search bar in the find tool.
Although CRISPR’s original use in Bacteria wasn’t for gene editing, its specific targeting using Guide RNA makes it a great candidate for gene editing in complex organisms like humans. CRISPR can render defective genes useless by cutting them at certain points, which is called making a knockout. CRISPR can also entirely replace mutated areas of genes by sending in a piece of template DNA along with the Guide RNA and CAS Protein. The template DNA’s ends will match the DNA regions bordering the gene-editing site. By using a process called homology-directed repair, the organism’s genome will exchange the DNA in the template strand to place the new gene in the area that has been removed by the CAS protein. Therefore, mutations in genes can be removed and exchanged for other DNA to make fully functional or improved genes.
Two Ways CRISPR Can Treat Parkinson's
Now that we understand how CRISPR works, it’s time to discover how this can be applied to Parkinson’s. Many diseases like Cystic Fibrosis and Sickle Cell Anemia are known as monogenic and require a single gene mutation to occur which is then passed down. With Parkinson’s, the situation is more complicated. There are multiple genetic pathways that cause Parkinson’s and there are two in particular that can be addressed using CRISPR technology.
1. Fixing Mutations in the SNCA Gene Which Cause Misfolding
Parkinson’s disease is caused by the buildup of proteins in the brain called alpha-synuclein which group together to form Lewy Bodies. The presence of Lewy Bodies obstructs normal brain function and is linked to serious conditions like dementia. The SNCA gene encodes alpha-synuclein and single base-pair mutations (such as changing an A to a G), commonly referred to as point mutations, are common causes of Parkinson’s. These mutations lead to protein misfolding because a wrong amino acid is translated. Once the protein misfolds, it can’t perform normal function and aggregates in the brain to form Lewy Bodies.
This is where CRISPR can come in. Single base pair mutations are the perfect problem for CRISPR to solve and the technology can easily be targeted to mutation sites. By fixing protein misfolding, normal alpha-synuclein function is restored, the progression of the disease halted, and Parkinson’s cured! Patients merely have to be screened for mutations and the problem can be solved before the disease has caused any negative effects.
2. Using CRISPR to regulate transcriptional activity of a-synuclein
Alpha-synuclein build up can also be caused by overexpression of SNCA genes. In some cases multiple copies of the gene are present or regulation of the gene has been altered to up-regulate it. Regulation of genes falls under the epigenome, or chemical factors which are added onto the genome that control its expression.
A common epigenetic control is methylation, or adding on methyl groups to areas of a gene. Lack of a methyl group signals the cell to express a gene more but by adding a methyl group (methylating) the expression can be lowered. Basically, the difference between a disease-causing gene being switched on or off could be a tiny group of atoms.
Although CRISPR is usually used to knockout DNA in the editing site, its unique targeting capability also helps it direct enzymes to regulate methylation. By adding the enzyme methyltransferase (which methylates) onto the CAS-Guide RNA complex, the enzyme can be directed to areas in need of methylation. SNCA can then be down-regulated and aggregation halted along with Parkinson’s.
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