2.1. Multiple system atrophy

Several common variations in the SNCA gene have been found to increase the risk of multiple system atrophy, a progressive brain disorder that affects movement and balance and disrupts the function of the autonomic nervous system. The autonomic nervous system controls actions that are mostly involuntary, such as regulation of blood pressure.

The identified gene variations each change a single DNA building block (nucleotide) in the SNCA gene. Researchers are working to determine whether these changes alter the function of alpha-synuclein and how they influence the risk of developing multiple system atrophy. Variations in the SNCA gene appear to affect disease risk in people of European descent; however, studies suggest that changes in this gene are not associated with multiple system atrophy in the Chinese population or in South Koreans. It is unclear whether SNCA gene variations are a risk factor for this condition in people of other geographic and ethnic backgrounds.

2.2. Dementia with Lewy bodies

At least six mutations in the SNCA gene have been found to cause dementia with Lewy bodies. This condition is characterized by intellectual decline (dementia); visual hallucinations; sudden changes in attention and mood; and movement problems characteristic of Parkinson disease (described below) such as rigidity of limbs, tremors, and impaired balance and coordination. A characteristic feature of this condition is Lewy bodies, which are abnormal clusters of alpha-synuclein protein in the brain. Lewy bodies also occur in Parkinson disease, but they tend to be more widespread in the brain in dementia with Lewy bodies.

In dementia with Lewy bodies, SNCA gene mutations lead to the production of an alpha-synuclein protein with an abnormal shape. The misshapen proteins cluster together, forming the main component of Lewy bodies. These protein clusters are present throughout the brain where they impair neuron function and ultimately cause cell death. Over time, the loss of neurons increasingly impairs intellectual and motor function and the regulation of emotions, resulting in the signs and symptoms of dementia with Lewy bodies.

2.3. Parkinson disease

At least 30 mutations in the SNCA gene have been found to cause Parkinson disease, a condition characterized by progressive problems with movement and balance. SNCA gene mutations are associated with the early-onset form of the disorder, which typically appears before age 50. Other variations in the SNCA gene have been found to increase the risk of developing Parkinson disease, although they do not appear to be a direct cause of the disease.

Researchers have described two types of alterations of the SNCA gene in people with Parkinson disease. One type changes single 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 A53T) or with the amino acid proline at position 30 (written as Ala30Pro or A30P). These alterations cause the alpha-synuclein protein to take on an incorrect 3-dimensional shape (misfold). In the other type of alteration, one of the two SNCA genes in each cell is inappropriately duplicated or triplicated. The extra copies of the SNCA gene lead to an excess of alpha-synuclein protein.

It is unclear how alterations in the SNCA gene cause Parkinson disease. This condition involves the selective death or impairment of neurons that produce dopamine. Misfolded or excess alpha-synuclein proteins may cluster together to form Lewy bodies and impair the function of these neurons in specific regions of the brain. Lewy bodies may disrupt the regulation of dopamine, which allows dopamine to accumulate to toxic levels and eventually kill neurons. Researchers also suspect that Lewy bodies stall or shut down the cell machinery that removes unneeded proteins. As a result, unneeded proteins may clog neurons and impair their functions. Symptoms of Parkinson disease appear when dopamine-producing neurons become impaired or die. The loss of these cells weakens communication between the brain and muscles, and ultimately the brain becomes unable to control muscle movement. The presence of Lewy bodies in a region of the brain called the substantia nigra, which controls balance and movement, are a characteristic feature of Parkinson disease.