SNCA

The SNCA gene provides instructions for making a small protein called alpha-synuclein. Alpha-synuclein is abundant in the brain, and smaller amounts are found in the heart, muscles, and other tissues. In the brain, alpha-synuclein localizes mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals. Within these structures, alpha-synuclein interacts with fats (lipids) and other proteins. Presynaptic terminals release chemical messengers, called neurotransmitters, from compartments known as synaptic vesicles.

Although the function of alpha-synuclein remains unknown, several studies suggest that it plays an important role in maintaining a supply of synaptic vesicles in presynaptic terminals. It may also help regulate the release of dopamine. Dopamine is a type of neurotransmitter that is critical for controlling the start and stop of voluntary and involuntary movements.

Parkinson disease - caused by mutations in the SNCA gene

Researchers have described two types of alterations of the SNCA gene that cause early-onset Parkinson disease. One type of alteration changes one of the protein building blocks (amino acids) used to make alpha-synuclein. In some cases, the amino acid alanine is replaced with the amino acid threonine at protein position 53 (written as Ala53Thr) or with the amino acid proline at position 30 (written as Ala30Pro). In a few cases, the amino acid glutamic acid is replaced with the amino acid lysine at position 46 (written as Glu46Lys). These mutations cause the alpha-synuclein protein to misfold, or take on an incorrect 3-dimensional shape. In the other type of alteration, one of the two SNCA genes in each cell is inappropriately duplicated or triplicated. Instead of the normal two copies of the SNCA gene, each cell has three or four copies, which leads to an excess amount of alpha-synuclein.

It is not clearly understood how alterations of the SNCA gene cause Parkinson disease, which is characterized by the selective death or impairment of neurons that produce dopamine. Mutated or excess alpha-synuclein proteins may cluster together (aggregate) and impair neuron functions in specific regions of the brain. For example, aggregated alpha-synuclein may disrupt the regulation of dopamine, which allows dopamine to accumulate to toxic levels and eventually kill the nerve cell. Researchers also suspect that misfolded or excess alpha-synuclein stalls or shuts down the cell machinery that removes unwanted proteins. As a result, unwanted proteins may clog the cell and impair neuron functions. Symptoms of Parkinson disease appear as an increased number of dopamine-producing neurons are impaired or die.

Misfolded alpha-synuclein is also a major component of Lewy bodies, abnormal deposits that appear in certain nerve cells in the brain. Lewy bodies in a region of the brain called the substantia nigra, which controls balance and movement, are a characteristic feature of Parkinson disease.

other disorders - caused by mutations in the SNCA gene

Researchers have identified mutations in the SNCA gene that may lead to a loss of intellectual functions (dementia). Two mutations cause a particular disorder known as dementia with Lewy bodies, in which dementia is associated with deposits of Lewy bodies in certain areas of the brain. Although the features of this disorder are variable, symptoms typically include dementia, visual hallucinations, fluctuations in attention, and changes characteristic of Parkinson disease such as trembling or rigidity of limbs, slow movement, and impaired balance and coordination.

One of the SNCA mutations responsible for dementia with Lewy bodies replaces the amino acid glutamic acid with the amino acid lysine at position 46 in the alpha-synuclein protein (written as Glu46Lys). The other mutation, which replaces the amino acid alanine with the amino acid threonine at position 53 (written as Ala53Thr), is associated with the features of both Parkinson disease and dementia with Lewy bodies.