Pathologies caused by ubiquitin and lysosomal pathway inhibition

Neurodegenerative diseases result from both Ubiquitin protease system (UPS) and lysosomal inhibition. If the UPS is inhibited proteins with a high turnover rapidly build up and many of these proteins aggregate which causes disease. The neurons are particularly sensitive to protein aggregates as evidenced by the many neurodegenerative diseases. An example of an inhibition of the UPS system is mutations to the Ubiquitin ligase (E3) gene parkin which render it non-functional. This leads to Parkinson’s disease [1]. The targets of Parkin aggregate and cause an alteration of dopamine metabolism which leads to oxidative stress and cell death. Another example of a neurodegenerative disease with a clear link to the UPS is Angelman’s syndrome [2]. Mutation in E6-AP a HECT domain ubiquitin ligase has been implicated in this illness and it is thought that the aggregation of this enzyme’s substrates probably results in the disease.  In some cases lysosomal degradation by autophagy can degrade protein aggregates as demonstrated by huntingtin and α-synuclein aggresomes, caused by overexpression of mutant forms of these proteins, which are effectively cleared from cells treated with rapamycin, an autophagy inducer, whereas treatment with 3-methyladenine, a potent autophagy inhibitor, reduces their clearance [3]. Therefore both pathways play a role in preventing protein aggregation and perturbations in either will lead to increased likelihood of developing aggregation related illnesses such as the neurodegenerative disease.

The UPS can play a major role in tumorigenesis however there is conflicting evidence over the lysosomal system. The UPS system degrades many of the proteins involved in controlling the cell cycle. The effect of a defect in the UPS system depends on the protein target. For example loss of Cyclin degradation could lead to a hyperactive cell cycle that promotes cancer. However the loss of function of the Ubiquitin E3 Mcm2 would lead to the build up of the tumour suppressor p53 and is likely to lead to cell cycle arrest [2].

Inhibition of UPS and lysosomal protein degradation can both affect development. Differentiation is controlled by rapidly turning over proteins and therefore any component that fails to be degraded at the correct time will disrupt development. For example loss of function of the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) in Caenorhabditis elegans zygotes result in a failure to establish the anteroposterior (AP) body axis [4]. This is due to a failure of the meiotic spindle to degrade as it is not ubiquitylated. Differentiation and development require large scale changes in a cell’s phenotype which will often result in obsolete organelles and protein complexes. For example erythroid maturation requires autophagy, which contributes to eliminate ribosomes or mitochondria after the expulsion of the nucleus [3].

Refs

  1. Hattori, N. and Mizuno, Y. 2004. Pathogenetic mechanisms of parkin in Parkinson’s disease. Lancet. 364:722–724.
  1. Nalepa, G. Rolfe, M. Harper, J.W. 2006. Drug discovery in the ubiquitin–proteasome system. Nat Rev Drug Disc. 5:596-613.
  1. Mariño, G. and López-Otín, C. 2004. Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci. 61:1439-1454.
  1. Bowerman, B. and Kurz, T. 2006. Degrade to create: developmental requirements for ubiquitin-mediated proteolysis during early C. elegans embryogenesis. Development. 133:773-784.
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