Proteins, clearance

As the ubiquitin proteasome pathway is a main route for protein clearance it is not surprising that in protein-opathies (disease caused by aggregate prone proteins) like sporadic Parkinson- or Huntington disease proteasome activity is reduced. Autosomal recessive loss of function of the E3 ligase parkin is the molecular base for one of the most common forms of familial Parkinson disease. 

Hastings RH, Folkesson HG, Matthay MA (2004) Mechanisms of alveolar protein clearance in the intact lung. Am J Physiol 286(4) L679-L689... 

Kang, D.E., Pietrzik, C.U., Baum, L., et al. (2000) Modulation of amyloid beta-protein clearance and Alzheimer s disease susceptibility by the LDL receptor-related protein pathway. J. Clin. Invest., 106, 1159-1166. 

Patil SP, Maki S, Khedkar S A, Rigby AC, Chan C. (2010) Withanohde A and asiatic acid modulate multiple targets associated with amyloid-P precursor protein processing and amyloid-p protein clearance. J Nat Prod 73 1196-1202. 

In all forms of glomerular nephritis in tropical populations in Africa, there was increased protein in the urine. In the selective proteinuria of the nephrotic syndrome most of the protein was mainly albumin and transferrin, with lower concentrations of IgG and other globulins. On the other hand, the urine of the nonselective proteinuria of the nephrotic syndrome is characterized by much higher concentrations of IgG, IgA, a2-macroglobulins, and some IgM. Differential protein clearance to establish selectivity of proteinuria has been discussed above. 

C7. Chandra, R. K., Manchanda, S. S., Srivastava, R. N., and Soothill, J. F., Differential protein clearances in Indian children with the nephrotic syndrome. Arch. Dis. Childhood 45, 491-495 (1970). 

For firms that manufacture several products from one source (e.g., Chinese hamster ovary [CHO] cells), a generic approach may suffice. Regulatory authorities in some countries are accepting this approach [13]. There are also some generic kits on the market that can be used to study host cell protein clearance during development, and may be considered acceptable for licensure. 

The rate of protein clearance has been estimated as 10% of the rate of fluid clearance from alveoli [173]. IgG clearance is probably mediated by FcRn transcytosis in distal type I alveolar epithelium and more proximal bronchial epithelium. Type I alveolar epithelium and bronchial epithelium contain the necessary subcellular structures for FcRn-mediated transcytosis vesicles, membrane invaginations, caveolae, and clathrin-coated pits [173,174], FcRn mRNA is expressed in lung although the cell types and locations have not yet been determined [112], Moreover, primary alveolar epithelial monolayer cell cultures express functional FcRn [173], plgA-R/SC transcytosis is thought to contribute little to distal (alveolar) airway IgG transport but might mediate more proximal (bronchial or bronchiolar) IgA transport [173], Uptake of an aerosolized IgG Fc-erythropoietin fusion molecule and subsequent erythropoietin-induced reticulocytosis has been demonstrated in human and nonhuman primates [175],... 

Disposition of paditaxel from plasma follows a biphasic elimination pattern. Approximately 97.5% of it is bound to plasma proteins. Clearance is triphasic and results mainly from hepatic extraction and biliary excretion. Eleven metabolites have been delected in plasma, but not identified. " ... 

Creatinine clearance is not usually a covariate for protein clearance. However, the kidney does form one site of clearance of proteins. Glomerular functionality and renal blood flow might be expected to have some impact on the clearance of low molecular weight proteins. For example, dose reductions are recommended in end stage renal disease patients receiving PEGylated interferon (52). However, accounts of reduced clearance in anuric patients are rare, suggesting that alternate routes of clearance are used in situations where renal function is nonexistent. 

Fig. 3 Mechanisms of neurodegeneration in PD. Pathogenic mutations may disrupt protein clearance mechanisms (e.g. autophagy) and alter protein expression, causing accumulation of misfolded proteins, such as a-synuclein. Protein aggregates may induce neurodegeneration. Oxidative stress caused by mitochondrial dysfunction may also initiate a cascade of events, including neuroinflammation, leading to neurodegeneration.

Berthiaume, Y., Broaddus, V. C., Gropper, M. A., Tanita, T., and Matthay, M. A. (1988) Alveolar liquid and protein clearance from normal dog lungs. J. Appl. Physiol. 65,585-593. Berthiaume, Y., Albertine, K. H., Grady, M., Pick, G., and Matthay, M. A. (1989) Protein clearance from the airspaces and lungs of unanesthetized sheep over 144 h. J. Appl. Physiol. 67, 1887-1897. 

Shukla, A. A., Jiang, C., Ma, J., Rubacha, M., Flansburg, L. and Lee, S. S. Demonstration of robust host-cell protein clearance in biopharmaceutical downstream process. Biotechnol. Prog. 24 615-622, 2008. 

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