Neurodegeneration risk factor,EIF2AK3 (PERK), influences tau protein aggregation

Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms—unfolded protein response and integrated stress response. Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling in vitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation, whereas inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the endoplasmic reticulum luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small-molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.     

Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18.

Linkage disequilibrium (LD) analysis has been promoted as a method of mapping disease genes, particularly in isolated populations, but has not yet been used for genome-screening studies of complex disorders. We present results of a study to investigate the feasibility of LD methods for genome screening using a sample of individuals affected with severe bipolar mood disorder (BP-I), from an isolated population of the Costa Rican central valley. Forty-eight patients with BP-I were genotyped for markers spaced at approximately 6-cM intervals across chromosome 18. Chromosome 18 was chosen because a previous genome-screening linkage study of two Costa Rican families had suggested a BP-I locus on this chromosome. Results of the current study suggest that LD methods will be useful for mapping BP-I in a larger sample. The results also support previously reported possible localizations (obtained from a separate collection of patients) of BP-I-susceptibility genes at two distinct sites on this chromosome. Current limitations of LD screening for identifying loci for complex traits are discussed, and recommendations are made for future research with these methods.     

INTERACTIVE EFFECTS OF GIBBERELLIC ACID AND SALINITY ON THE GROWTH OF BEANS

Nieman , R. H., and Leon Bernstein . (U. S. Salinity Laboratory, Riverside, Calif.) Interactive effects of gibberellic acid and salinity on the growth of beans. Amer. Jour. Bot. 46(9): 667–670. 1959.—Dwarf red kidney bean plants, grown from the primary leaf stage to maturity on a graded salt series (0, 1.5, 3.0 and 4.5 atm. O.P. NaCl added to a base nutrient solution), showed a progressive and highly significant growth depression with increasing concentration of NaCl. At low levels of salinity (0 and 1.5 atm. O.P.), gibberellic acid applied as a spray to primary leaves, in concentrations of 10 and 100 p.p.m. in distilled water, increased the stem length, fresh and dry wt. of both the top and the root, the yield of green beans, area per leaf, and the total leaf area per plant. At high levels of salinity (3.0 and 4.5 atm. O.P.) growth was so severely suppressed that the expression of all gibberellin effects, except the increase in stem length, was essentially prevented. Gibberellin was, therefore, ineffective in overcoming the salt-induced suppression of growth. An increased rate of water use per unit leaf area was quite consistently observed with the gibberellin-treated plants. This may be simply the result of the increased exposure to light and to air movement of leaves on an elongated stem.     

OSMOTIC ADJUSTMENT OF PLANTS TO SALINE MEDIA. II. DYNAMIC PHASE

Bernstein , Leon . (U. S. Salinity Lab., Riverside, Calif.) Osmotic adjustment of plants to saline media. II. Dynamic phase. Amer. Jour. Bot. 50(4): 360–370. Illus. 1963.—The time-course of osmotic adjustment in bean and pepper plants to increased salinity of the medium was determined by periodic sampling of plants following salt additions to the medium. Bean plants adjusted to increases of 1 atm OP within a day, the adjustment in roots occurring primarily at night following salt addition at 6 pm , whereas leaves and stems made most of their adjustment in the daytime. Pepper plants did not adjust completely to 1.5 atm NaCl additions in 48 hr, but OP increased by about the same amount in both species (0.5—1.0 atm per day). Diurnal fluctuations in OP of leaves and stems of both species and in roots of pepper were matched by parallel fluctuations in K concentrations. Added NaCl caused increased concentrations of K in leaves and stems which were more or less replaced by more slowly absorbed ions, Ca and Mg in bean leaves and Na in bean stems. Other salts produced comparable immediate effects on K level, but K was replaced more rapidly if the cation added was readily accumulated by the bean (Ca). In roots, Na uptake predominated if Na salts were added but K uptake was important on the CaCl₂ treatment. The K effects suggest a passive distribution of K between the cell and the medium.