Genetics: Mutations in Parkinson disease pathology

Neurodegeneration, the continuous loss of neuronal structure and function, is responsible for a number of mental illnesses, including Parkinson disease and Alzheimer disease. In both of these diseases, the aggregation of specific proteins leads to the death of neurons and the disruption of normal brain function. Researchers studied a German family with a history of Parkinson disease in order to better understand the pathology of the disease. Figure 1 shows a pedigree analysis of the family, where shaded individuals have developed Parkinson disease.

Figure 1 Pedigree analysis

Upon studying biopsies obtained from diseased family members, the researchers found an abnormal aggregation of α-synuclein in the brain. Although the exact function of α-synuclein currently unknown, the protein is thought to be normally involved in spatial learning, working memory, synaptic rearrangement, and dopamine regulation. Figure 2 shows a pedigree analysis o the German family, where shaded individuals have developed Parkinson's disease.

Upon PCR analysis, it was discovered that a mutation in the ubiquitin carboxy-terminal hydrolase L1 gene (UCH-L1) was present in the family members that had Parkinson disease. The isoleucine at position 93 (codon ATC) was changed to a methionine (codon ATG). Researchers then expressed the mutant and wild-type UCH-L1 proteins in E. coli cells. The catalytic activity of each protein is shown in Table 1.

Table 1 Catalytic activity and molecular weight of the wild-type or mutant protein; U = 1 μmol min${}^{-1}$‍

Immunohistochemistry of midbrain sections of a patient with Parkinson disease showed α-synuclein and UCH-L1 double-positive Lewy bodies, abnormal protein aggregates in mesencephalon dopaminergic neurons, suggesting physical and/or functional interaction between the two proteins leads to Parkinson disease.