Clinical, Pathogenesis

Detection of somatic single nucleotide variants and other small mutations in alpha-synuclein in multiple system atrophy brain

The cause of MSA remains unknown, although aggregation of the alpha-synuclein protein into “clumps” plays a key role. Mutations (DNA changes) are not an obvious candidate to explain this, as it is not inherited. There is increasing evidence, however, that DNA in the brain may acquire mutations, termed “somatic”, during development or ageing. This leads to our brains being “mosaics”, made of many small different pieces. One type of mutation is a “spelling mistake”, a change of a single “letter” in the code that makes the building blocks of the protein. This could change its structure, making it prone to aggregation. Alternatively, extra copies of the alpha-synuclein gene could increase protein levels, also causing aggregation.

We previously reported extra copies of the alpha-synuclein gene in some brain cells from individuals who had lived with MSA or Parkinson’s. We found more cells with mutations in a brain region in the MSA type where this region is more severely affected. Additionally, cells with extra gene copies had alpha-synuclein clumps more often. These findings suggest that these mutations contribute to the disease. We are investigating this further by focusing on the main cells affected in MSA (oligodendrocytes).

As most cells did not have these mutations, we have clearly not fully explained the cause of MSA. We will now target the “spelling mistakes” in alpha-synuclein by sequencing this gene at very high “coverage” in different brain regions. This means that, even if the mutation is present in only around 1% of cells, we will be able to find it. If we do find such mutations, we will have demonstrated an additional piece in the puzzle of why MSA develops. This will lead to studies to determine the exact cells that get them, and how they affect the protein and the cells that carry them.