Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype.

A gene for autosomal recessive parkinsonism, PARK2 (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early-onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult-onset, clinically typical tremor-dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinson's disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa-induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late-onset typical Parkinson's disease.

Simple redox-linked proton-transfer design: new insights from structures of quinol-fumarate reductase.

The mitochondrial bioenergetics field has experienced an exciting breakthrough with the recent structure determination of several key membrane complexes. The latest addition to this line of structures, that of quinol-fumarate reductase, provides new insights into the mechanism of energy transduction.

Natural engineering principles of electron tunnelling in biological oxidation-reduction.

We have surveyed proteins with known atomic structure whose function involves electron transfer; in these, electrons can travel up to 14 A between redox centres through the protein medium. Transfer over longer distances always involves a chain of cofactors. This redox centre proximity alone is sufficient to allow tunnelling of electrons at rates far faster than the substrate redox reactions it supports. Consequently, there has been no necessity for proteins to evolve optimized routes between redox centres. Instead, simple geometry enables rapid tunnelling to high-energy intermediate states. This greatly simplifies any analysis of redox protein mechanisms and challenges the need to postulate mechanisms of superexchange through redox centres or the maintenance of charge neutrality when investigating electron-transfer reactions. Such tunnelling also allows sequential electron transfer in catalytic sites to surmount radical transition states without involving the movement of hydride ions, as is generally assumed. The 14 A or less spacing of redox centres provides highly robust engineering for electron transfer, and may reflect selection against designs that have proved more vulnerable to mutations during the course of evolution.

Biological electron transfer.

Many oxidoreductases are constructed from (a) local sites of strongly coupled substrate-redox cofactor partners participating in exchange of electron pairs, (b) electron pair/single electron transducing redox centers, and (c) nonadiabatic, long-distance, single-electron tunneling between weakly coupled redox centers. The latter is the subject of an expanding experimental program that seeks to manipulate, test, and apply the parameters of theory. New results from the photosynthetic reaction center protein confirm that the electronic-tunneling medium appears relatively homogeneous, with any variances evident having no impact on function, and that control of intraprotein rates and directional specificity rests on a combination of distance, free energy, and reorganization energy. Interprotein electron transfer between cytochrome c and the reaction center and in lactate dehydrogenase, a typical oxidoreductase from yeast, are examined. Rates of interprotein electron transfer appear to follow intraprotein guidelines with the added essential provision of binding forces to bring the cofactors of the reacting proteins into proximity.

Rat uterine tissue and cell responses to the presence of plain and indomethacin-delivering IUDs.

Plain silastic intrauterine devices or those containing 270 micrograms of indomethacin were inserted into the caudal portion of one uterine horn of mature Wistar rats. After a 3-week period animals were fixed by perfusion on the morning of day 2 after estrus. Segments of uterine tissue corresponding to regions adjacent to and cranial to the devices as well as an equivalent portion of the contralateral horn were embedded in glycol methacrylate. A group of control animals without any form of device were treated in an identical manner. Sections cut from these segments were evaluated by grid-point stereology to ascertain changes in tissue volumes and cell populations. It was found that the presence of plain devices induced hypertrophy in the stroma and myometrium of the portion of the uterus adjacent to the device. The presence of indomethacin in such devices prevented stromal hypertrophy. No changes in populations of fibroblasts or areas of glandular or vascular tissue were evident in any treatment group. Cell populations of neutrophils, eosinophils, and mononuclear cells, however, were elevated in the superficial stroma of the horns bearing either type of device; this feature was more pronounced for neutrophils in the presence of the indomethacin devices. Neutrophils, rather than eosinophils, predominated in the epithelia of the uterus bearing either type of IUD. Conversely, eosinophil populations were reduced in the superficial tissues cranial to the devices delivering indomethacin. Neutrophils and mononuclear cells were also found to be elevated in the deep stroma of tissues adjacent to both the plain and medicated device.