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This Week in PNAS
BIOPHYSICS
How α-synuclein aggregates in Parkinson's disease
Carlos Bertoncini et al. report how α-synuclein changes its conformation and forms aggregates that appear to contribute to Parkinson's disease. The protein α-synuclein can aggregate and form Lewy bodies in motor cells of the brain stem, causing the subsequent death of these cells and development of Parkinson's disease. The authors investigated the protein's structure and conformational changes using paramagnetic relaxation enhancement and NMR dipolar couplings and found that solitary α-synuclein is strongly stabilized by sequences that prevent oligomerization and aggregation. High temperatures and polyamines could destabilize the protein's configuration, leading to a completely relaxed, uncoiled strand. This opening of the inner core exposes hydrophobic sections of the protein, which group together to form the long β-sheets that can become protofibrils, and then larger aggregates. These strands can aggregate easily, leading to the bundles that may cause Parkinson's disease. The authors suggest that the release of intrinsic structure in the α-synuclein monomer is the key step that triggers oligomerization and aggregation.
“Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein” by Carlos W. Bertoncini, Young-Sang Jung, Claudio O. Fernandez, Wolfgang Hoyer, Christian Griesinger, Thomas M. Jovin, and Markus Zweckstetter (see pages 1430-1435)
DEVELOPMENTAL BIOLOGY
Estrogen receptor α controls prostate development
Yoko Omoto et al. report that estrogen receptor α (ERα) regulates prostate growth during the first 2 weeks of life. Previous studies have shown that brief, neonatal exposure to estrogen permanently programs prostate development, leading to increased incidence of intraepithelial neoplasia (uncontrolled, progressive epithelial cell multiplication) with aging. However, in ERα knockout mice, the prostate grows normally after estrogen exposure. Using immunohistochemistry, the authors evaluated ER profiles in the mouse ventral prostate (VP) during the first 4 postnatal weeks. During week 1, the researchers observed that ERα was abundant in the stroma but was restricted to the epithelium by week 2. By week 4, ERβ completely replaced ERα in the epithelium. The researchers injected 2-week-old mice with 3βAdiol, a ligand for ERs in the VP, and discovered that proliferation increased almost 2-fold. Because ERα is the only receptor form present in the VP at 2 weeks of age, these results suggest that 3βAdiol acts on ERα to signal cell proliferation. Furthermore, in ERα knockout mice, morphogenesis of VP ducts was abnormal, with a reduced number of secondary branches. The authors conclude that, during the first 2 postnatal weeks, estrogen acts on ERα in both the epithelium and stroma of the VP, potentially affecting cell proliferation and duct development.
“Estrogen receptor α and imprinting of the neonatal mouse ventral prostate by estrogen” by Yoko Omoto, Otabek Imamov, Margaret Warner, and Jan-Åke Gustafsson (see pages 1484-1489)
IMMUNOLOGY
Light chains exacerbate asthma
Hyperresponsiveness leading to airway constriction in asthma may be triggered by a portion of the immune system itself—antibody light chains. Aletta Kraneveld et al. showed previously that free light chains can mediate allergic hypersensitivity responses in the skin; thus, for this study, they hypothesized that free light chains might play a role in allergic asthma, which is characterized by inflammation stemming from mast cell activation. The researchers sensitized mice to a specific, inhaled trigger. Upon exposure to the trigger, mice treated with a free light chain antagonist did not develop asthma symptoms, such as airway constriction. The researchers also found that the light chains, on their own, were able to induce mast cell degranulation and bronchoconstriction. Studies of human sera showed that the presence of light chains in patients with asthma is higher than in patients without asthma, suggesting that anti-light chain therapy could present a strategy for treating asthma.
“Elicitation of allergic asthma by immunoglobulin free light chains” by Aletta D. Kraneveld, Mirjam Kool, Anneke H. van Houwelingen, Paul Roholl, Alan Solomon, Dirkje S. Postma, Frans P. Nijkamp, and Frank A. Redegeld (see pages 1578-1583)
MICROBIOLOGY
Understanding cholera outbreaks
Researchers have found that cholera epidemics are temporally linked to the absence of vibriophages in the environment that kill cholera bacteria. Cholera is a persistent public health problem in many developing countries, and outbreaks caused by toxigenic Vibrio cholerae of the O1 or O139 serogroups occur with seasonal regularity in the Ganges Delta region of Bangladesh and India. Drinking water is a vehicle for transmission, but factors controlling the level of V. cholerae O1 and O139 in aquatic environments remain unclear. Shah Faruque et al. found that, over a 3-year period in Dhaka, Bangladesh, the number of V. cholerae cells in water increased whenever the number of vibriophages decreased. Similarly, cholera epidemics tended to end concurrent with large increases in the concentration of these viruses in the water. This finding suggests that the presence of phages is a factor that causes V. cholerae populations in aquatic environments to wax or wane in a recurrent cycle. According to the authors, monitoring the level of cholera phages could be useful in tracking outbreaks, predicting epidemics, and anticipating emergence of new strains.
“Seasonal epidemics of cholera inversely correlate with the prevalence of environmental cholera phages” by Shah M. Faruque, Iftekhar Bin Naser, M. Johirul Islam, A. S. G. Faruque, A. N. Ghosh, G. Balakrish Nair, David A. Sack, and John J. Mekalanos (see pages 1702-1707)
PSYCHOLOGY
Rapid visual memory decay in mild cognitive impairment
Zhong-Lin Lu et al. report that the rapid decay of iconic (visual short-term) memory appears to be a general characteristic of mild cognitive impairment, which often precedes the onset of Alzheimer's disease. Iconic memory typically lasts only a fraction of a second before it is either lost or stored in short-term memory, and a link between iconic memory impairment and Alzheimer's disease has been suggested. The authors tested the iconic memory of 23 young adults (average age, 20 years), 11 older adults with mild cognitive impairment (average age, 85 years), and 16 older controls (average age, 82 years). Iconic memory was characterized by using the partial report paradigm with the same visual stimuli parameters in each observation group. The researchers found that mean iconic memory duration was significantly shorter in subjects with mild cognitive impairment (0.07 s), compared with both older (0.30 s) and younger (0.34 s) controls. In a series of conventional neuropsychological tests used to assess cognitive function, the mild cognitive impairment group performed significantly worse than the older control group. In both of these groups, no significant performance differences were observed in visual and task abilities or the ability to transfer items to short-term memory. The authors suggest that testing iconic memory could be used with other measures to aid the diagnosis of Alzheimer's disease.
“Fast decay of iconic memory in observers with mild cognitive impairments” by Zhong-Lin Lu, James Neuse, Stephen Madigan, and Barbara Anne Dosher (see pages 1797-1802)
Figures and Tables
Native-state conformations of α-synuclein.
VP branching morphology of ERα-/- mice.
Mast cell degranulation induced by light chains.
Cholera phage types.
