From the Guidelines
Cytoplasmic inclusions are caused by the accumulation of mutant proteins, such as alpha-1 antitrypsin (AAT) Z protein, within the endoplasmic reticulum (ER) of cells.
Key Factors
- The mutant AAT Z protein has an increased tendency to form polymers through a loop-sheet insertion mechanism, leading to the formation of inclusions in the ER 1.
- The accumulation of these polymers causes cytotoxicity and cellular injury, resulting in the formation of inclusions 1.
- The quality control apparatus of the cell, including molecular chaperone proteins, recognizes the abnormal mutant AAT Z polypeptide and directs it to a pathway of retention within the ER, rather than allowing export from the cell 1.
Mechanism
- The exact relationship between AAT Z polymerization and hepatocellular injury remains unclear, but it is thought that the accumulation of mutant protein in the ER triggers a retention signal, leading to cellular injury 1.
- The formation of inclusions is influenced by factors such as the rate of protein synthesis, degradation, and interactions with other proteins, as well as environmental factors such as viral infections 1.
Clinical Implications
- The accumulation of mutant AAT Z protein in the ER is associated with an increased risk of developing cirrhosis and liver disease in individuals with AAT deficiency 1.
- Understanding the mechanisms of protein accumulation and inclusion formation is crucial for the development of therapeutic strategies to prevent or reverse liver disease in AAT deficiency 1.
From the Research
Causes of Cytoplasmic Inclusions
- Exposure to stress, particularly oxidative stress, can lead to misfolding of proteins and the formation of cytoplasmic protein aggregates 2
- Misfolded proteins can accumulate and form inclusions due to the cell's inability to refold or degrade them 2
- The presence of p62, a protein that binds to misfolded and ubiquitinated proteins, is a common feature of cytoplasmic inclusions 2
- Impairment in protein degradation by the proteasome can lead to increased protein levels and the formation of cytoplasmic inclusions 3
- Abnormal aggregation of intermediate filaments can also contribute to the formation of cytoplasmic inclusions 4
- The accumulation of α-Synuclein, a protein that can form conformationally distinct "strains" with varying behavioral characteristics and toxicities, is a key feature of Multiple system atrophy (MSA) and can lead to the formation of oligodendroglial cytoplasmic inclusions 5
Factors Contributing to Cytoplasmic Inclusion Formation
- Oxidative stress 2
- Protein misfolding 2, 3
- Impairment in protein degradation by the proteasome 3
- Abnormal aggregation of intermediate filaments 4
- Accumulation of α-Synuclein 5
- Interplay between oligodendrocytes, neurons, and α-Synuclein 5