13 March 2003. Mitochondrial malfunction underlies the pathological damage seen in fruit fly models of Parkinson's disease, researchers report in this week's PNAS online. The paper adds to the growing body of evidence linking this intracellular organelle to neurodegeneration (see ARF related news story; also ARF news story).
Joint first authors Jessica Greene and Alexander Whitworth in Leo Pallanck’s laboratory at the University of Washington, Seattle, collaborated with Mel Feany’s lab at Harvard Medical School to make a Drosophila model of Parkinson's disease in which the parkin genes were ablated. Loss of parkin activity causes a particularly aggressive, early-onset form of PD in humans. These parkin knockouts die after 27 days instead of the typical 39 days. They also have severe locomotor defects—that is, they can’t fly and climb as well as controls. In addition, the male parkin knockouts are completely sterile.
To pinpoint what went awry in these animals, the researchers added active parkin back to selected tissues. Parkin expression in the mesoderm restored the flies’ flight and climbing abilities, prompting the authors to examine the role of parkin in muscle, one of the major mesodermal tissue types. In the major flight muscles of the parkin knockouts, the authors found an overall decrease in the density of the muscle fibers and gross deformity of the mitochondria. The cristae—invaginations of the inner membrane that are crucial to the production of the energy for muscle contraction—were particularly affected. Significantly, Greene and Whitworth found that the mitochondrial damage came first. Microscopic examination revealed malformed cristae even at the pupal stage, when muscle fibers still appeared normal.
In Parkinson's disease, degeneration of dopaminergic neurons in the brain’s substantia nigra is responsible for much of the pathology and symptoms. In this fly model, however, most dopaminergic neurons were unaffected, except for those in the dorsomedial section of the brain, which shrank and lost the dopamine-synthesizing enzyme tyrosine hydroxylase as the flies aged.
This work comes close on the heels of a paper just published online by the American Journal of Human Genetics, which suggests that certain nucleotide variations in mitochondrial DNA may protect individuals from Parkinson's. Duke University's Jeffrey Vance and colleagues examined these variations between the mitochondrial genomes of 609 PD patients and 340 controls. First author Joelle Van der Walt and coworkers found that specific single nucleotide polymorphisms, or SNPs, are found in the group without the disease. One SNP in particular, which causes an amino acid change from threonine to alanine in the mitochondrial enzyme NADH dehydrogenase, is strongly associated with the protective effect. "Future biochemical studies will be needed to confirm the functional significance of these associations," write the authors.—Tom Fagan.
Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83. Abstract
Van der Walt JM, Nicodemus KK, Martin ER, Scott WK, Nance MA, Watts RL, Hubble JP, Haines JL, Koller WC, Lyons K, Pahwa R, Stern MB, Colcher A, Hiner BC, Jankovic J, Ondo WG, Allen Jr FH, Goetz CG, Small GW, Mastaglia F, Stajich JM, McLaurin AC, Middleton LT, Scott BL, Schmechel DE, Pericak-Vance MA, Vance JM. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet. 2003 Apr;72(4):804-11. Abstract