Rett protein MeCP2 seen to affect protein tied to Parkinson’s

MeCP2, the protein impaired in most cases of Rett syndrome, controls the production of alpha-synuclein, a protein implicated in Parkinson’s disease, a study reports.

Alpha-synuclein production was highest when the MeCP2 protein carried mutations from Rett patients with symptoms similar to those of Parkinson’s, data showed.

“MeCP2 is most likely involved in the regulation of [alpha-synuclein] expression and, moreover, two MeCP2 variants might be associated with [Parkinson’s disease] features observed in [Rett] patients,” the scientists wrote.

The study, “The Alpha-Synuclein Gene (SNCA) is a Genomic Target of Methyl-CpG Binding Protein 2 (MeCP2)—Implications for Parkinson’s Disease and Rett Syndrome,” was published in the journal Molecular Neurobiology.

Rett motor and gait symptoms can be similar to those of Parkinson’s disease

Most Rett cases stem from mutations in the MECP2 gene, which encodes the MeCP2 protein. This protein is found at high levels in mature nerve cells and regulates the activity, or expression, of other genes, thereby influencing brain development and function.

Motor and gait disease symptoms typically emerge when patients are between 1 and 4 years old. In some cases, they resemble hallmarks of Parkinson’s disease — namely, rigidity, tremors, and slow movement (bradykinesia).

Similar to Parkinson’s patients, people with Rett are known to have fewer cells in the brain producing the chemical messenger dopamine, as well as lower levels of dopamine in the cerebrospinal fluid, which surrounds the brain and spinal cord.

For these reasons, genes implicated in the development of Parkinson’s may be regulated by MeCP2, a team led by scientists at the University of Bonn, in Germany, suggest.

To find out, the team investigated whether MeCP2 regulates the expression of the SNCA gene, which encodes alpha-synuclein, an abundant protein found mainly in the brain. Misfolded alpha-synuclein is the main component of Lewy bodies, which are protein clumps thought to cause the death of dopamine-producing nerve cells in Parkinson’s.

MeCP2 protein suppresses gene expression by binding to regions of DNA that have been methylated, which means adding a methyl chemical group to cytosines followed by guanines, two of the building blocks of DNA. The researchers first identified five potential MeCP2 binding sites along the SNCA gene.

Using DNA isolated from human nerve cells, MeCP2 was found to bind to a region of the SNCA gene called intron 1, and its binding depended upon the degree of DNA methylation. Notably, DNA isolated from the brain tissue of Parkinson’s patients showed far lower levels of SNCA gene methylation than did tissue from people without the disease.

MeCP2 protein levels affected production of the alpha-synuclein protein

Experiments then confirmed that MeCP2 suppressed SNCA gene expression by binding to a specific subregion of SNCA intron 1.

Single changes in the DNA sequence adjacent to the SNCA intron 1 subregion, which altered methylation, were found to increase or decrease the binding of MeCP2 and alpha-synuclein expression.

Accordingly, when MeCP2 was deleted from cells, alpha-synuclein protein levels rose threefold, a result the researchers considered striking, whereas MeCP2’s overproduction significantly reduced alpha-synuclein production.

Altering the MeCP2 protein to carry one of the two most common Rett-causing mutations — R255X and T158M — had no effect on alpha-synuclein protein levels. In contrast, MeCP2 carrying mutations from Rett patients with Parkinson’s-like features — A140D and, particularly, R270X — significantly increased alpha-synuclein expression.

Of all the MeCP2 mutations evaluated, R270X showed the weakest binding to the methylated subregion of SNCA intron 1, resulting in a loss of control over the alpha-synuclein expression, the team suggested.

“We identified the methylation of SNCA intron 1 as an important factor for binding of MeCP2 and the regulation of a-syn [alpha-synuclein] expression,” the researchers wrote. “Altered DNA binding properties of specific MeCP2 variants [mutations] increased a-syn expression, implicating dysregulated expression of SNCA in the pathology of these [Rett] genotypes.”