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Protein misfolding diseases

Cells produce proteins in ribosomes. To be useful, these chains must fold into exactly the right three-dimensional structure.

Some twenty unrelated diseases as Alzheimer disease, type II diabetes, Creutzfeldt-Jakob disease (CJD) and "mad cow" disease (BSE) - are known to date - are all caused by protein misfolding. These different diseases share several common biochemical and biophysical characteristics.

In all cases, normal correctly folded cellular proteins progressively aggregate and undergo a major structural transition from their normal structure into an abnormal beta-sheet-rich conformation.

Most protein misfolding diseases occur spontaneously at a specific stage of life, usually old age.

Occasionally, there is also a genetic contribution, in which the aggregation-prone proteins have a different amino-acid sequence than that found in the general population. Such mutations can lead to an unusually early onset of misfolding diseases.

For example, a "Flemish mutation" in the beta-amyloid peptide can lead to the early onset of Alzheimer’s disease, a "Japanese mutation" in the islet amyloid polypeptide (IAPP) can lead to the early onset of type 2 diabetes, and mutations in the prion protein (PrP) can lead to inherited forms of CJD and other diseases.

Since these pathogenic protein aggregates are resistant to disaggregation by standard disinfecting agents, they could conceivably infect patients via contaminated surgical and dental instruments.

The group’s findings regarding the von Hippel Lindau (VHL) tumor-suppressor protein clearly indicates that abnormal folding and stability play a central role in the malfunction of many VHL mutants.

Pathogenesis

Defects in protein folding may underlie some of these depositions in a variety of unrelated diseases. Nascent polypeptide chains of proteins, made on ribosomes, are ultimately arranged into either α helices or β sheets, and the proper configuration of these arrangements (protein folding) is critical to the individual protein’s function and its transport into cell organelles.

In the process of folding, partially folded intermediates arise, and these may form intracellular aggregates among themselves or by entangling other proteins.

Under normal conditions, however, these intermediates are stabilized by a number of molecular chaperones, which interact with proteins directly.

Chaperones aid in proper folding and in transport across the ER, Golgi complex, and beyond. Some chaperones are synthesized constitutively and affect normal intracellular protein trafficking, whereas others are induced by stress, such as heat (heat-shock proteins, e.g., hsp70, hsp90), and "rescue" shock-stressed proteins from misfolding.

If the folding process is not successful, the chaperones facilitate degradation of the damaged protein. This degradative process often involves ubiquitin (also a heat-shock protein), which is added to the abnormal protein and marks it for degradation by the proteasome complex. There are several mechanisms by which protein folding defects can cause intracellular accumulations or result in disease.

Defective intracellular transport and secretion of critical proteins

In α1-antitrypsin deficiency, mutations in the protein significantly slow folding, resulting in the build-up of partially folded intermediates, which aggregate in the ER of the liver and are not secreted. The resultant deficiency of the circulating enzyme causes emphysema.

In cystic fibrosis, mutation delays dissociation of a chloride channel protein from one of its chaperones, resulting in abnormal folding and loss of function (Chapter 10). In familial hypercholesterolemia, mutations in low-density lipoprotein receptors interfere with proper folding of receptor proteins.

ER stress induced by unfolded and misfolded proteins

Unfolded or misfolded proteins accumulate in the ER and trigger a number of cellular responses, collectively called the unfolded protein response.

The unfolded protein response is mediated by several proteins that reside in and span the ER membrane. The luminal domains of these proteins sense perturbations in protein folding, and the cytoplasmic domains activate signaling pathways that reduce the levels of misfolded proteins in the cell, by increasing the production of chaperones and slowing down protein translation.

Paradoxically, the activation of the unfolded protein response also leads to cell death by activating caspases, particularly an ER-resident caspase called caspase-12 (CASP12).

Thus, misfolded proteins initially trigger the cytoprotective function of this response, but if these abnormal proteins persist, the pro-apoptotic cytotoxic functions take over. Aggregation of abnormally folded proteins, caused by genetic mutations, aging, or unknown environmental factors, is now recognized as a feature of a number of neurodegenerative diseases, including Alzheimer disease, Huntington disease, and Parkinson disease, and possibly type II diabetes.

Deprivation of glucose and oxygen, and stress such as heat, also result in protein misfolding and trigger the unfolded protein response, culminating in cell injury and death.

Aggregation of abnormal proteins

Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions. The deposits can be intracellular, extracellular, or both, and there is accumulating evidence that the aggregates may either directly or indirectly cause the pathologic changes. Certain forms of amyloidosis fall in this category of diseases. These disorders are sometimes called proteinopathies or protein-aggregation diseases.