Cells constantly work to maintain balance, known as cellular homeostasis, by managing proteins. Damaged or misfolded proteins are cellular “waste” that can disrupt normal processes if they accumulate. To address this, cells employ sophisticated systems to identify, contain, and eliminate these problematic molecules.
What Aggresomes Are
An aggresome is a specialized cellular structure that forms when a cell’s protein quality control systems are overwhelmed. It functions as a collection point for misfolded and aggregated proteins that the cell cannot immediately repair or degrade. These structures are dense cytoplasmic inclusions, typically located near the cell’s nucleus, around the microtubule-organizing center (MTOC) or centrosome.
The composition of an aggresome includes the aggregated proteins, which are often tagged with ubiquitin for degradation. Aggresomes also contain components of the cellular machinery involved in protein folding and degradation, such as chaperone proteins and proteasomes. A distinctive feature is the cage-like structure of intermediate filaments, like vimentin, that often surrounds the aggresome, helping to contain its contents.
How and Why Aggresomes Form
Aggresome formation is a regulated cellular response triggered by conditions leading to an excessive accumulation of misfolded proteins. This occurs when protein folding mechanisms are strained, degradation pathways like the ubiquitin-proteasome system are impaired, or during cellular stress such as hyperthermia or the overexpression of certain insoluble proteins. When normal refolding or degradation processes are insufficient, misfolded proteins begin to aggregate.
These initial protein aggregates are then actively transported to a central location within the cell to form the aggresome. This transport relies on microtubules and specific motor proteins, primarily the dynein/dynactin motor complex. Proteins like histone deacetylase 6 (HDAC6) and Bcl-2-associated athanogene 3 (BAG3) link these misfolded proteins to the transport machinery. This directed movement concentrates the aggregates at the pericentriolar region, forming the distinct aggresome structure.
Aggresomes and Disease
While aggresome formation is a protective mechanism designed to sequester and facilitate the clearance of harmful protein aggregates, its failure or chronic overload can contribute to various diseases. When the cellular capacity for aggresome formation or subsequent clearance mechanisms, like autophagy, are overwhelmed, the persistent accumulation of these protein aggregates becomes detrimental. This dysfunction is particularly relevant in age-related neurodegenerative disorders.
In Alzheimer’s disease (AD), aggresomes are implicated in the accumulation of misfolded proteins such as amyloid-beta (Aβ) and hyperphosphorylated tau (p-Tau). Aβ monomers can assemble into degradation-resistant aggresomes, and p-Tau aggresome formation involves microtubule motor proteins for transport. Neurofibrillary tangles, composed of tau protein, are a hallmark of AD, and their formation mechanisms are linked to the cellular response to protein misfolding.
Parkinson’s disease (PD) is another neurodegenerative condition where aggresome-like structures, known as Lewy bodies, are a pathological feature. These inclusions contain aggregated alpha-synuclein and other proteins like Parkin. The inability to clear misfolded alpha-synuclein can lead to its aggregation within aggresomes, contributing to neuronal dysfunction and death.
Huntington’s disease (HD) involves the accumulation of an abnormally expanded huntingtin (HTT) protein. Mutant HTT forms aggresome-like perinuclear inclusions, and its aggregation can exhaust the ubiquitin-proteasome system, leading to further accumulation. The formation and persistence of these aggregates contribute to the neurodegeneration seen in HD. In amyotrophic lateral sclerosis (ALS), cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark, with aggresome formation contributing to their aggregation. The presence of these persistent, uncleared aggresomes in neuronal cells underscores the consequences when the cell’s waste management system is overwhelmed.