alpha-synuclein
The first PD-related gene to be identified was alpha-synuclein. Researchers at NIH and other institutions studied the genetic profiles of a large Italian family and three Greek families with familial PD and found that their disease was related to a mutation in this gene. They found a second alpha-synuclein mutation in a German family with PD. These findings prompted studies of the role of alpha-synuclein in PD, which led to the discovery that Lewy bodies from people with the sporadic form of PD contained clumps of alpha-synuclein proteins. This discovery revealed a potential link between hereditary and sporadic forms of the disease and sparked investigations into the normal function of alpha-synuclein as well as the possible effects of alpha-synuclein mutations on normal cellular activity
One theory about how alpha-synuclein is associated with PD holds that the mutated protein interferes with cell membranes. Within the cell body, individual molecules of alpha-synuclein join together to form tiny protein threads called fibrils; this process is called fibrillization. Investigators at the Brigham and Women's Hospital Udall Center and elsewhere have shown that mutations in the alpha-synuclein gene disrupt the fibrillization process and lead to the accumulation of protofibrils, an intermediate step in alpha-synuclein fibrillization. They found that alpha-synuclein protofibrils have protein structures which resemble bacterial and insect toxins that make membranes leaky. This could trigger cell death and may explain the toxicity of Lewy body proteins. This idea is supported by studies from the Massachusetts General Hospital and Massachusetts Institute of Technology Udall Center showing that alpha-synuclein is located near cell membranes in postmortem brain tissue from people with diffuse Lewy body disease.
Another study suggests that a buildup of normal alpha-synuclein may clog up the cell's protein disposal system and cause neurons to die. A group of researchers at NIH and other institutions investigated a rare familial form of early-onset PD and discovered that a multiplication of the normal alpha-synuclein gene, and a corresponding increase in alpha-synuclein protein, can cause the disease. The researchers analyzed blood samples from a family, the "Iowa kindred," in which many relatives developed PD or related neurological diseases. In the relatives with PD, the researchers found four copies of the alpha-synuclein gene — an abnormal triplication of three alpha-synuclein genes on one copy of chromosome 4 and one gene on the other chromosome 4 — instead of the usual two copies of the alpha-synuclein gene. This multiplication resulted in an abnormally large amount of alpha-synuclein in the cells
A third theory proposes that mutant alpha-synuclein interferes with the normal housekeeping functions of cells and lets proteins build up to toxic levels. Researchers at the Columbia University Udall Center, along with colleagues at Brigham and Women's Hospital and the Albert Einstein College of Medicine, have found that normal alpha-synuclein is broken down by lysosomes, which act as the cell's garbage disposal system. Mutant alpha-synuclein, however, blocks the pathway into the lysosomes. This inhibits the breakdown of alpha-synuclein as well as other proteins. This may trigger a toxic buildup of protein “garbage” inside the cell.
Researchers are continuing to study the alpha-synuclein gene to clarify how it affects PD.
For example, Mayo Clinic Udall Center researchers are assessing the alpha-synuclein gene in a large group of people with PD, and in a control group of healthy people who match the PD patients in age, gender, and demographics, in order to look for variations in the gene that may affect susceptibility to the disease. Investigators at the Johns Hopkins University Udall Center have developed mice with alpha-synuclein gene mutations and found that the mice accumulate alpha-synuclein in the midbrain, cerebellum, brainstem, and spinal cord and develop an adult-onset neurodegenerative disease with symptoms resembling human PD, including motor dysfunction, bradykinesia, and dystonia.