14 March 2004. A report in press in the Journal of Biological Chemistry, published online February 24, adds to the growing body of evidence that traces the etiology of Parkinson's disease to the mitochondria. Jie Shen and colleagues at Brigham and Women's Hospital, Boston, reveal that many mitochondrial proteins are downregulated in mice lacking the protein parkin.
Parkin mutations, of course, have been linked to familial, early-onset Parkinson's disease since 1998 (see ARF related news story). Being a ubiquitin ligase, parkin has been generally thought to protect against this devastating disease by preparing other proteins for destruction. Much research has, therefore, focused on the relationship between parkin and proteins that end up in Lewy bodies. These are intracellular inclusions that foul up dopaminergic neurons of the substantia nigra, the part of the brain most affected by Parkinson's. However, in fruit fly models of the disease made by ablating parkin, dopaminergic neurons are hardly affected, while muscle mitochondria seem particularly compromised (see ARF related news story). More recently, Shen has shown that knocking out the gene in mice causes some physiological changes to the substantia nigra, but without the decimation of neurons that is observed in humans, and without altering likely parkin substrates, such as α-synuclein and synphilin (see Goldberg et al., 2003). So in mice, what are the biochemical consequences of losing parkin?
To address this issue, joint first authors James Palacino and Dijana Sagi adopted a comparative proteomics approach. They prepared extracts from the substantia nigra of both parkin-negative and normal mice, then separated the proteins by large, two-dimensional electrophoresis. When they analyzed these chromatographs, they could identify about 8,000 proteins, of which only 15 varied quantitatively between the two samples. Fourteen of these were downregulated in the parkin-deficient animals.
To identify these proteins, the authors subjected them to mass spectroscopy, and were surprised to find that nine of the 14 proteins are mitochondrial. Five are involved in oxidative phosphorylation, while four are involved in managing oxidative stress. The results suggest that parkin plays a major role in maintaining mitochondrial function. In support of this, the authors found that the parkin-deficient mice gained weight more slowly, had decreased serum antioxidant capacity, and increased protein and lipid peroxidation compared to normal animals. The last finding, in particular, suggests that parkin somehow protects against reactive oxygen species. As these are, for the most part, produced in the mitochondria, parkin may somehow prevent their production, possibly by maintaining flow through the electron transport chain; the authors also found that mitochondrial respiration is reduced in the mutant mice.
All told, these findings bolster the view that Parkinson's disease is connected with mitochondrial fitness. MPTP, for example, has been used for years to induce an experimental disease that models Parkinson's, and this chemical attacks the mitochondria, as does rotenone, a pesticide chemical that induces Parkinson's-like symptoms (see ARF related news story). And several groups have reported hints that polymorphisms in the DNA that is often forgotten—mitochondrial DNA—can alter the risk of Parkinson's disease (Van der Walt, 2001; Ross et al., 2003; Tanaka, 2002).—Tom Fagan.
Palacino JJ, Sagi K, Goldberg MS, Krauss S, Motz C, Klose J, Shen J. Mitochondrial dysfunction and oxidative damage in Parkin-deficient mice. PNAS 2004 January 9;303:197-202. Abstract