Cytotoxicity of Aberrant Proteins

A typical mammalian cell has approximately10–10 individual protein molecules represented by around 10–10 distinct proteins. In order for this enormous ensemble of proteins to coordinately carry out the biochemical processes critical to the life of a cell, they must be highly organized. Cellular organization spans multiple levels (Figure 1) including structural, spatial, temporal and quantitative dimensions that collectively define a cell’s morphology and physiology. Indeed, most differences between diverse cell types such as a neuron and hepatocyte are largely due to both the ensemble and organization of their constituent proteins. Hence, there is an intimate relationship between protein organization and cellular function. Conversely, cellular dysfunction is often the result of aberrant proteins falling outside a cell’s normal organizational scheme. Thus, proteins that are structurally flawed, mislocalized, expressed at the wrong time, or present in the wrong amounts are all defined as aberrant and can impact cellular function in many ways that range from inconsequential to catastrophic. Remarkably, aberrant proteins arise all the time by any of numerous mechanisms: intrinsic limitations in the fidelity of biosynthetic, trafficking and degradation pathways; extrinsic influences such as changes in temperature, pH, oxidation or salinity; exposure to protein-damaging agents; or in rare circumstances, inherited genetic mutations. To deal with this constant barrage, cells have evolved numerous ‘quality control’ (QC) mechanisms to recognize and destroy aberrant proteins. Nonetheless, constant aberrant protein production in many conditions, especially over long time periods, can lead to disruptions of normal cellular homeostasis that eventually contribute to disease. The various mechanisms by which aberrant proteins lead to cellular dysfunction and disease will be the topic of this article. Rather than cataloging a series of incompletely understood and disparate diseases caused by aberrant proteins, we will focus on general principles. By considering the normal pathways of protein biosynthesis, trafficking and metabolism (Part I), we hope to illustrate how and why deviations from the norm lead to aberrant protein production, and the mechanisms by which they can cause cellular dysfunction (Part II). Each of these basic cell biological principles will be highlighted by specific examples taken from diseases that are the direct consequence of aberrant proteins generated frommutated genes. No single disease can best exemplify all of the mechanisms, and no unifying mechanism is likely to fully explain any one disease, much less all diseases. Instead, by understanding the general framework for the possible ways in which aberrant proteins can cause cellular dysfunction, the concepts outlined here can be used to formulate rational models of pathogenesis for individual diseases on a case-by-case basis.