Rebecca Boyer

Bio: Rebecca Boyer is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Ubiquitin & Ubiquitin C-Terminal Hydrolase. The author has an hindex of 5, co-authored 5 publications receiving 8634 citations.

Mutation in the α-synuclein gene identified in families with Parkinson's disease

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

The ubiquitin pathway in Parkinson's disease

Abstract: Mutations of the α-synuclein gene1,2 have been identified in some familial forms of Parkinson's disease, and α-synuclein protein has been shown to accumulate in the brains of patients with the disease3. These findings suggest that Parkinson's disease may be caused by the abnormal aggregation of α-synuclein protein. Here we have identified in a German family with Parkinson's disease a missense mutation in the ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene. We show that this mutation, Ile93Met, causes a partial loss of the catalytic activity of this thiol protease, which could lead to aberrations in the proteolytic pathway and aggregation of proteins.

Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome.

Abstract: Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.

Intron-exon structure of ubiquitin c-terminal hydrolase-L1.

Abstract: Parkinson's disease (PD) is a common neurodegenerative movement disorder characterized by tremor, bradykinesia, postural instability and muscular rigidity. Neuropathologically, it is defined by cell loss in the substantia nigra associated with the presence of intraneuronal inclusions called Lewy bodies (LB) and processes engorged with proteinaceous material, the Lewy neurites. The recent identification of mutations in the a-synuclein gene in some familial forms of PD 3 ' 6 and the demonstration of accumulation of the protein in Lewy bodies and Lewy neurites 7 suggest that abnormal protein aggregation may cause the disease. In addition to asynuclein, LBs contain ubiquitin, proteasomal subunits 2 and ubiquitin C-terminal hydrolase-Ll, 5 pointing to a potential participation of the ubiquitin-proteasome degradation pathway in the onset of the disease. We confirmed this hypothesis by identifying a missense mutation in the ubiquitin C-terminal hydrolase LI (UCH-L1) gene in a German family with an autosomal dominant form of PD. 4 UCH-L1 is highly specific for neurons and cells of the diffuse neuroendocrine system, and represents 1% to 5% of the total brain protein extract. 8 Northern blot analysis reveals a 1.3-kb brain-specific transcript broadly represented in all areas of the brain tested, particularly in the substantia nigra (Fig. 1). Enzymes belonging to the ubiquitin C-terminal hydrolases family can remove small amides and esters at the carboxyl terminus of ubiquitin and have been shown to hydrolyze peptides and small proteins similarly (reviewed in 9). They contribute to the pool of free monomeric ubiquitin molecules by hydrolysing the ubiquitin polymeric proprotein or ubiquitin-ribosomal fusion proteins during the maturation of the ribosome. 9 The Ile93Met mutation observed in 2 PD patients 4 causes a partial loss of catalytic activity of the UCH-L1 enzyme which could induce aberrations in the degradation pathway and lead to aggregation of proteins. To permit the rapid screening for mutations and assess the UCH-L1 role in PD, we have established specific amplification assays for all of its coding exons.

Contig Map of the Parkinson's Disease Region on 4q21-q23

Abstract: We have constructed a yeast artificial chromosome contig (YAC) map of human chromosome 4q21q23 across the Parkinson's disease region by combining molecular and fluorescence in situ hybridization techniques. This map contains 55 YACs and 51 molecular markers, including 23 polymorphic markers. We have also isolated one PI and 33 bacterial artificial chromosomes located within this contig. Plasmid libraries were generated from 11 of these BAC and PI clones, and 614 random plasmid clones were sequenced for a total of about 200 kb. This contig allowed us to precisely determine the location of 18 transcripts within the D4S2460-D4S2986 interval, including the alpha-synuclein gene found to be mutated in some families with Parkinson's disease.

Initial sequencing and comparative analysis of the mouse genome.

Abstract: The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Abstract: Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.

Abstract: The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

Abstract: Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, conside...