The maintenance of functional proteins in a cell relies upon, at the simplest level, balancing protein synthesis with protein degradation to sustain steady-state protein levels. The ways that the cell accomplishes this are complex and includes the regulation of protein synthesis, folding, trafficking, maintenance, and degradation. This highly evolved process, known as protein homeostasis or proteostasis is a fundamental process that has evolved to maintain a healthy and functional set of proteins (a proteome). Since proteins carry out the majority of the work in the cell, regulating proteostasis is a critical task to maintain a healthy cell. In turn, deterioration of the proteostasis network has broad effects on cellular function.

Aging represents a challenge to maintaining proteostasis. Declining function of protein quality control mechanisms combined with increasing damage to proteins result in significant stress and challenge the proteostasis network. While the proteostasis network has evolved to respond to stress on the proteome, a combination of challenges that occur during the aging process often overwhelms these safe-guards and can result in cellular dysfunction and death.

This collapse in proteostasis is no more apparent than in late-onset neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis, and the prion diseases. Each of these disorders is characterized by the unnatural production of aberrant proteins that challenge and ultimately overwhelm the proteostasis network resulting in severe cellular dysfunction. A hallmark of disrupted proteostasis in these diseases is the aggregation of the aberrant proteins in specific neurons in the brain. While the proteins that aggregate are unrelated and the neurons affected differ between disorders, in each case neurons become dysfunctional and ultimately die.

The correlation between protein aggregation and neuronal death has initially led to the idea that aggregates were causing the cellular dysfunction and ultimate neuronal death associated with these diseases. Some research supports this correlation but the past ten years have revealed a much more nuanced understanding of the role of protein aggregates in aging and disease. As it turns out, some types of large aggregates that form in the cell actually protect the cell from the toxicity, while some smaller forms of aggregated protein are much more toxic. Ultimately, there is much work to be done in defining the types and consequences of protein aggregates that form in cells during each individual proteinopathy, and more broadly, cellular aging.

HEK293T cells aggregate an overexpressed expanded huntingtin-GFP fusion protein (right) but not corresponding wild-type huntingtin-GFP fusion protein.

HEK293T cells (human embryonic kidney cells) display aggregated expanded huntingtin protein shown as concentrated green dots (right) but not corresponding wild-type unexpanded huntingtin protein shown as diffuse green staining (left).

So why worry about protein aggregation and proteostasis? Promoting cellular proteostasis is potential therapeutic method to promote healthy aging. Scientists have already shown that methods that decrease protein synthesis, activate protein quality control pathways, and increase protein degradation can increase the lifespan of animals in a lab setting. By striving to understand how these processes contribute to healthy aging, we hope to uncover therapeutic targets to promote proteostasis and ultimately, healthspan. In future posts I hope to discuss topics that relate to proteostasis and aging highlighting current research both from the Buck Institute and the broader research community.