How a Cell Deals with Abnormal Proteins

Abstract

Defective protein folding is responsible for many diseases. Although these diseases seem to be quite diverse at the first glance, there is evidence for common pathogenetic principles. The basis of the pathological changes is the cell’s inability to prevent protein misfolding, to revert misfolded proteins to normal or to eliminate misfolded proteins by degradation. This could result in deposition of potentially cytotoxic protein aggregates (protein aggregation diseases). Chronic degenerative diseases of the central nervous system (e.g. Alzheimer’s and Parkinson’s disease), the amyloidoses, but also chronic liver diseases, for example alcoholic and nonalcoholic steatohepatitis, belong to this category of disorders. This review highlights general pathogenic principles of protein aggregation diseases based on immunohistochemical and biochemical studies as well as observations in a mouse model for protein aggregation in the context of alcoholic and nonalcoholic steatohepatitis. The cellular defense mechanisms involved in protein quality control as well as the pathogenesis of protein aggregation diseases will be discussed.

Nonproliferative and Proliferative Lesions of the Rat and Mouse Endocrine System

“…( Aigelsreiter et al 2007 ; Frith et al 2000 ; Greaves 2012b ; Höppener et al 1994 ; Inoue and Kisilevsky 1996 ; Johnson et al 1992 ; Leiter and Herbert 1996 ; Majeed 1993 ; Solomon et al 1999 ; Wong et al 2008 )…”

Protein Quality Control During Erythropoiesis and Hemoglobin Synthesis

“…Basic principles of protein quality control are discussed briefly here and reviewed more extensively elsewhere (2-4, 6-8). Even under optimal circumstances, protein misfolding occurs frequently in all cells through “off-pathway” folding of otherwise normal polypeptides and random biosynthetic errors.…”

“…Disorders of protein aggregation have mainly been characterized in the central nervous system, but also involve numerous other tissues including liver, heart and pancreas (see Table 2 and (2, 4, 9, 10, 15, 18) for reviews). Despite divergent affected cell types and clinical features, several common themes emerge.…”

“…Numerous diseases ensue when the levels of unstable proteins exceed tissue capacities for quality control. Excessive protein misfolding, aggregation and consequent toxicities are linked to the pathogenesis of numerous diseases affecting nervous system, heart, pancreas, liver and other tissues (reviewed in (2-4)). In β-thalassemia, abundant excess α globin is destabilized by several mechanisms, including deficiency of its natural binding partner and autocatalytic oxidative stress.…”

Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer

“…Since protein structure and function are coupled, misfolded proteins are, at first, loss-of-function proteins that might reduce cell viability, in particular when generated in larger quantities. A more dangerous feature of misfolded proteins, however, lies in their strong tendency toward abnormal protein–protein interactions or aggregations, which is reflected by the involvement of misfolded proteins and their aggregates in several amyloidotic diseases, including neurodegenerative syndromes such as Alzheimer’s disease and Parkinson’s disease ( 13 , 14 ). The fact that several of these intracellular and extracellular protein aggregates contain β-sheet-like structures and form filamentous structures also supports the notion that misfolded proteins are not necessarily structureless protein coils or unspecific aggregates, at least when they are formed by homogenous proteins as in the case of several neurodegenerative diseases ( 13 ).…”