Parkinson’s Disease—A New Mutation Leads to Potential New Insights Into Disease Pathogenesis

Abstract & Commentary

Synopsis: The findings also support further investigations with agents, which may modify mitochondrial function, and exert antioxidative effects such as coenzyme Q10.

Source: Valente EM, et al. Hereditary Early-Onset Parkinson’s Disease Caused By Mutation in PINK1. Science. 2004:304:1158-1160.

Parkinson’s disease is a progressive neurodegenerative illness that affects about 1 million people in North America. Although environmental risk factors have received considerable attention, the importance of genetics to understanding susceptibility to Parkinson’s disease is increasingly recognized. Familial forms of Parkinson’s disease are rare, and account for less than 10% of cases. However, the identification of single gene mutations have led to new insights which have implicated both abnormal protein aggregation as well as oxidative damage in disease pathogenesis. The present report is that of a new form of hereditary early-onset autosomal recessive Parkinson’s disease, which is caused by mutations in PINK1 (PTEN)-induced kinase 1. Valente and colleagues identified 2 homozygous mutations affecting the PINK1 kinase domain in 3 consanguineous PARK6 families. A truncating nonsense mutation and a missense mutation were found in a highly conserved amino acid. Valente et al demonstrated that PINK1 was localized to mitochondria, and that mutations in the kinase resulted in a reduction in mitochondrial membrane potential, as well as increased vulnerability to apoptosis induced by inhibitors of the proteasome. These findings are, therefore, the first direct evidence linking a nuclear encoded protein, which is localized to mitochondria to Parkinson’s disease pathogenesis. These findings correlate with a large body of other evidence suggesting that mitochondrial dysfunction contributes to Parkinson’s disease. The models of Parkinson’s disease produced by MPTP and rotenone both specifically inhibit complex 1 activity of the electron transport gene.

Genetic studies have also implicated oxidative stress in Parkinson’s disease pathogenesis. Mutations in DJ-1 cause autosomal recessive early-onset Parkinson’s disease. DJ-1 is a protein that participates in the oxidative stress response. Mutations in the protein render cells more vulnerable to oxidative damage. It is known that oxidative damage leads to crosslinking of proteins such as a-synuclein. A-Synuclein is both oxidatively modified as well as nitrated in Parkinson’s disease. Dopamine can also generate the highly reactive dopamine quinones which can form adducts with proteins such as a-synuclein and crosslink them, facilitating their aggregation. Inhibition of complex 1 may also impair the ubiquitin proteasome protein degradation pathway by causing oxidative damage to proteins, perhaps including components of proteasomes.


Converging evidence implicates both protein aggregation as well as oxidative damage in mitochondrial dysfunction in Parkinson’s disease pathogenesis. It is likely that these factors may interact. The discovery of the mutations in PINK1 provide further evidence that mitochondrial dysfunction might play a key role in disease pathogenesis. What the normal function of PINK1 is within mitochondria however, remains to be determined. It is not known what its substrates are or how it directly affects mitochondrial function. Nevertheless, the discovery of this mutation may lead to improved animal models, as well as novel insights into Parkinson’s disease pathogenesis. The findings also support further investigations with agents, which may modify mitochondrial function, and exert antioxidative effects such as coenzyme Q10. — M. Flint Beal

Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.