Targeted Disruption of the PME-1 Gene Causes Loss of Demethylated PP2A and Perinatal Lethality in Mice

Phosphoprotein phosphatase 2A (PP2A), a major serine-threonine protein phosphatase in eukaryotes, is an oligomeric protein comprised of structural (A) and catalytic (C) subunits to which a variable regulatory subunit (B) can associate. The C subunit contains a methyl ester post-translational modification on its C-terminal leucine residue, which is removed by a specific methylesterase (PME-1). Methylesterification is thought to control the binding of different B subunits to AC dimers, but little is known about its physiological significance in vivo.Here, we show that targeted disruption of the PME-1 gene causes perinatal lethality in mice, a phenotype that correlates with a virtually complete loss of the demethylated form of PP2A in the nervous system and peripheral tissues. Interestingly, PP2A catalytic activity over a peptide substrate was dramatically reduced in PME-1(-/-) tissues, which also displayed alterations in phosphoproteome content.These findings suggest a role for the demethylated form of PP2A in maintenance of enzyme function and phosphorylation networks in vivo

Symptoms of Knee Instability are Risk Factors for Recurrent Falls.

OBJECTIVES: Whether knee instability contributes to the increased risk of falls and fractures observed in persons with knee osteoarthritis (OA) has not been studied. We examined the association of knee buckling with the risk of falling and fall-related consequences in older adults with, or at high risk for, knee OA. METHODS: At the 60 month visit of the Multicenter Osteoarthritis Study, men and women ages 55 to 84 were asked about knee buckling in the past 3 months and whether they fell when a knee buckled. Falls and fall-related injuries in the past 12 months and balance confidence were assessed at 60 and 84 months. Multivariate logistic regression was used to assess the association of knee buckling with falls and their consequences. RESULTS: 1,842 subjects (59% women, mean [SD] age= 66.9 [7.8] and BMI= 30.3 [5.7]) were included. At 60 months 16.8% reported buckling and at 84 months 14.1% had recurrent (≥2) falls. Bucklers at 60 months had a 1.6 to 2.5-fold greater odds of recurrent falls, fear of falling and poor balance confidence at 84 months. Those who fell when a knee buckled at baseline had a 4.5-fold, 2-fold and 3-fold increased odds two years later of recurrent falls, significant fall injuries and fall injuries that limited activity, respectively, and were 4 times more likely to have poor balance confidence. CONCLUSION: Interventions that reduce knee buckling may help prevent falls, fall-related injuries and adverse psychological consequences of falls in persons with knee OA