The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases
ABSTRACT Mutations in the leucine-rich kinase 2 gene (LRRK 2) encoding dardarin, on chromosome 12, are a common cause of familial and sporadic Parkinson's disease. The most common mutation, a heterozygous 6055 G>A transition (G 2019 S) accounts for approximately 3--10% of familial Parkinson's disease and 1--8% sporadic Parkinson's disease in several European-derived populations. Some families with disease caused by LRRK 2 mutations have been reported to include patients with highly variable clinical and pathological features. We screened for the most common LRRK 2 mutation in a series of patients with Parkinson's Disease, Alzheimer's disease, Progressive Supranuclear Palsy, Multiple System Atrophy and frontotemporal dementia, as well as in neurologically normal controls. The mutation was found only in Parkinson's disease patients or their relatives and not in those with other neurodegenerative disease.
- [Show abstract] [Hide abstract]
ABSTRACT: This paper describes the application of evolvable hardware to the design of a widely-used power electronics device, comparing the automatically synthesized circuits with those designed using the latest conventional design methods. With the increasing need by digital devices for low voltage and high current battery-driven power supplies, considerable research effort in recent years has been spent on high-efficiency DC-DC power converters. The best solution so far has been the use of control-driven synchronous rectifiers in these converters, which can yield efficiencies in the range of 91 to 92 percent. It is possible, however, that other designs could be found which might result in even higher efficiencies, with lower voltage and higher current outputs. Since the mid 1990's, the use of evolutionary algorithms to design a variety of hardware systems has seen rapid and successful growth, frequently resulting in novel designs not possible by conventional design techniques. In an exploratory experiment we will apply evolutionary methods to design a high efficiency, low voltage, high current output DC-DC converter. The performance of this evolved design will be compared with that of the control-driven synchronous rectifier converter, designed using conventional electronics design methods. While evolutionary design will not remove the fundamental design challenges, it is hoped that improved design approaches will emerge from the experiments. The paper explains why achieving high efficiencies in low output voltage DC-DC converters faces fundamental problems. A variety of solutions developed in the last 20 years are examined. Then the development of evolutionary processes starting in the 1950's is described. The invention of the field programmable gate array (FPGA) in the 1980's enabled extension of the evolutionary process to hardware design. Following this section, the need for and invention of hardware platforms more suitable for hardware evolution than the FPGA is reviewed. The series of experiments which is the objective of this paper is described, followed by comparisons which will be made between evolved and conventionally designed low voltage output DC-DC converters. The comparisons will be based on: maximum achieved efficiency; number of runs requi- red to evolve to maximum efficiency; complexity of required hardware circuits; and other parameters found to be important as the experiments are performed. Sufficient details of the hardware and software used, and a complete list of references will be given, to enable duplication of the experiments and results by other independent research workers. On completion of the experiments, results will be analyzed and conclusions drawn as to whether the use of evolutionary design methods result in advantages over conventional design techniques.Telecommunications Energy Conference, 2004. INTELEC 2004. 26th Annual International; 10/2004
- JAMA Neurology 02/2006; 63(1):156-7. DOI:10.1001/archneur.63.1.156 · 7.01 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) recently have been identified as the most common genetic cause of late-onset sporadic and familial Parkinson's disease (PD). The studies herein explore the biological and pathological properties of Lrrk2. Genetic analysis was performed to identify autopsied patients with the most common Lrrk2 mutation (G2019S). Using an antibody specific to Lrrk2, the biochemical and immunocytochemical distribution of Lrrk2 was assessed. Three patients with the G2019S Lrrk2 mutation were identified. Two patients demonstrated classic PD with Lewy bodies, although concurrent pathological changes consistent with Alzheimer's disease were also present in one of these individuals. The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2. Lrrk2 accumulations were unique to this patient and Lrrk2 was not detected in other types of pathological inclusions. Biochemical analysis showed that Lrrk2 is predominantly a soluble approximately 250 kDa cytoplasmic protein expressed throughout the brain but also in many other organs. The reasons for the selective predisposition of patients with mutations in LRRK2 to develop parkinsonism remains unclear, but Lrrk2 mutations may prime select neuronal populations to cellular insults that can lead to aberrant protein aggregation.Annals of Neurology 02/2006; 59(2):315-22. DOI:10.1002/ana.20791 · 11.91 Impact Factor