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Unit 2: Lesson 1

Foundation 1: Biomolecules

Neurodegeneration and genome mutations


Neurodegeneration is the continuous loss of neuronal structure and function and is responsible for a number of mental illnesses, particularly Parkinson disease and Alzheimer disease. Both of these illnesses are characterized by the presence of Lewy bodies, or aggregated protein deposits in the brain. Recent studies have explored the underlying cause of neurodegeneration in Parkinson disease and the mechanism of the malfunction on a cellular level.
In one such study, a German family with a history of Parkinson’s disease exhibited an abnormal aggregation of a-synuclein, an abundant protein in the brain. Although its exact function is currently unknown, the protein is thought to be involved in spatial learning, working memory, synaptic rearrangement, and dopamine regulation.
Upon PCR analysis, it was discovered that a mutation in the ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene was present in family members with Parkinson’s disease. The isoleucine at position 93 (codon ATC) was changed to a methionine (codon ATG). The mutant protein demonstrates a roughly 50% reduction in catalytic activity compared to the wild-type protein (Table 1).
Table 1 The catalytic activity of the wild-type and mutant protein when expressed in E. coli and presented with the substrate. The weight of each protein is also included. (U) = 1 μmol minstart superscript, minus, 1, end superscript
Wild-type UCH-L1 proteinMutant UCH-L1 protein
Catalytic activity4.08 U mgstart superscript, minus, 1, end superscript2.41 U mgstart superscript, minus, 1, end superscript
Weight of protein24.8 kDa24.8 kDa
It has been shown that UCH-L1 gene exhibits an autosomal dominant inheritance trend. Figure 2 below shows a pedigree analysis in the German family, where shaded individuals have developed Parkinson's disease.
Figure 2 Pedigree analysis
Immunohistochemistry of midbrain sections of a patient with Parkinson’s disease showed a-synuclein and UCH-L1-double-positive Lewy bodies in mesencephalon dopaminergic neurons, suggesting physical and/or functional interaction between the two proteins in patients with Parkinson’s disease.
Source: Leroy, E. Boyer, R. Auburger, G. Leube, B. Ulm, G. Mezey, E. et al. (1998). The ubiquitin pathway in Parkinson's disease. Nature, 451-452.
Yasuda T1, Nihira T, Ren YR, Cao XQ, Wada K, Setsuie R. et al. (2009).Effects of UCH-L1 on alpha-synuclein over-expression mouse model of Parkinson's disease. Journal of neurochemistry, 932-944.
Which of the following most likely explains the inheritance pattern shown in the pedigree?
Choose 1 answer:
Choose 1 answer: