Fight Aging!

The most common and well-researched age-related neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, and so forth, are associated with the aggregation of proteins into harmful solid deposits in the brain, usually also associated with a secondary halo of toxic and out of place molecules. Some few proteins can misfold or become altered by post-translational modifications in ways that encourage other molecules of the same protein to become altered in the same way, and join together to form growing structures. The plaque formed from misfolded amyloid-β is one example, the neurofibrillary tangles formed by hyperphosphorylated tau another. In some cases, as for α-synuclein in Parkinson's disease, the altered protein spreads from cell to cell in a prion-like way, producing dysfunction as it goes.

In today's open access paper, researchers look into one aspect of the regulation of aggrephagy, a form of autophagy targeted to protein aggregates. Autophagy flags unwanted structures in the cell, engulfing them into a membrane called an autophagosome, and then transporting it to a lysosome where it merges to allow the cargo to be broken down by lysosomal enzymes. Upregulation of autophagy to produce benefits to health is a popular topic, though efforts to produce drugs targeting autophagy have not progressed all that much past calorie restriction mimetics such as rapamycin. The hope here is that finding a way to specifically upregulate aggrephagy could slow the progression of neurodegenerative conditions driven by pathological protein aggregation; it remains to be seen as to how well this approach works in practice.

The essential role of CCT2 in the regulation of aggrephagy

Protein aggregation, the abnormal accumulation of misfolded or unfolded proteins, is a ubiquitous phenomenon associated with numerous human pathologies, including neurodegenerative diseases, metabolic disorders, and cancer. These aggregations often lead to cellular dysfunction and, ultimately, tissue damage and organ failure. To combat this threat, cells have evolved intricate mechanisms to maintain protein homeostasis (proteostasis), including the molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy. Among these, autophagy, particularly aggrephagy - a subtype of autophagy specifically targeting protein aggregates - has garnered significant attention due to its pivotal role in the clearing toxic protein aggregates.

Chaperonin Containing TCP-1 (CCT) is a multi-subunit protein complex essential for the folding of approximately 10% of cytosolic proteins. CCT is composed of eight distinct subunits (CCT1-8), each playing a critical role in maintaining the structural integrity of nascent polypeptides. Among these, CCT2, a subunit of CCT, has recently emerged as a novel player in the regulation of aggrephagy, shedding light on the intricate interplay between protein folding and degradation

This mini review outlines CCT2's dual roles: as a molecular chaperone crucial for protein folding and homeostasis, and recently, as an autophagy receptor in aggrephagy, degrading solid protein aggregates to maintain proteostasis. We detail CCT2's mechanisms in aggrephagy, emphasizing its interplay with cellular clearance machinery. The selectivity of CCT2-mediated aggrephagy for solid aggregates has implications for neurodegenerative diseases. Further research is warranted to explore the therapeutic potential of enhancing CCT2-mediated aggrephagy in such diseases.