More Insight Into How Cells Clear Protein Aggregates

Proteins, the basis for all cellular machines, are very complex structures. Their properties depend upon correct folding, and so misfolded proteins are essentially broken, unable to perform their functions. Some forms of misfolded or otherwise damaged proteins can precipitate from cell and tissue fluids to form solid aggregates. The presence of these aggregates is a form of damage, and cellular quality control mechanisms toil constantly to recycle or repair broken proteins. Clearly these mechanisms fail or are overwhelmed with advancing age, as growing levels of aggregated and misfolded proteins are one of the hallmarks of old tissue. Researchers are investigating in ever greater detail how exactly cells act to clear aggregates, with the goal of finding ways to enhance these evolved processes. The research noted in this post is one example among many, in which the scientists look beyond chaperone proteins, such as heat shock proteins, that are responsible for enabling correct folding and prevention of aggregates, and focus on how the activities of these chaperones are coordinated.

The presence of many of types of aggregate are associated with specific age-related conditions, especially neurodegenerative diseases such as Parkinson's disease (aggregates of α-synuclein) and Alzheimer's disease (aggregates of one of the many types of amyloid). The evidence for aggregates as a direct cause of pathology varies in quality, but there is nonetheless considerable funding and energy directed towards the development of therapies to clear these aggregates. In Alzheimer's disease, for example, forms of immunotherapy are under development to attempt to manipulate immune cells into attacking and recycling the damaged proteins making up aggregates.

At this point the prospects for effective treatments via enhancement of existing cellular quality control mechanisms, as opposed to other forms of clearance such as immunotherapy, seem more distant. It is clearly an interesting proposal, as many ways of slowing aging in laboratory species have been shown to be accompanied by increased activity of chaperone proteins, clearance of damaged proteins, and recycling of cellular components. Calorie restriction is among these, to pick one example. Despite more than a decade of serious interest in finding therapies to boost the activity of quality control processes there is as of yet little progress towards clinical trials or drug candidates, however. Perhaps that will change when a new and more tractable point of influence is discovered in the relevant areas of cellular biochemistry, or perhaps it is another of those areas where progress is a matter of hard work and funding, but too few research groups are presently interested in this approach to generate real traction. For my part, I am more in favor of targeted clearance from the outside via strategies such as immunotherapy rather than attempting to alter existing cellular operations; the latter tends to be much harder to accomplish safely and without side-effects. On the other hand, more competition and diversity in research strategies is usually a good thing.

How Human Cells Can Dissolve Damaging Protein Aggregates

Proteins in all cells - from bacteria to human - are folded in their native state. Proteins are first manufactured as long, sequential chains of amino acids and must assume a specific three-dimensional structure, i.e., fold, to be functional. This correctly folded state, or protein homeostasis, is at constant risk from external and internal influences. Damaged proteins lose their structure, unfold and then tend to clump together. If such aggregates form, they can damage the cells and even cause the cells to die, which we see in neurodegenerative diseases such as Alzheimer's and Parkinson's, and even in ageing processes. The formation of protein aggregates in different organs of the human body is associated with a large number of diseases, including metabolic disorders.

"Dissolving protein aggregates is a critical step in recycling defective proteins and providing protection against stress-induced cell damage. We had several clues as to the main players in this process, but we didn't know exactly how it worked." The researchers succeeded in identifying a previously unknown, multi-component protein complex that efficiently solubilizes stress-induced protein aggregates in vitro. This complex consists of molecular folding helpers, the chaperones, which in this case belong to the heat shock protein 70 (Hsp70) class. These are proteins that aid other proteins in the folding process.

The researchers also studied the co-chaperones that regulate Hsp70 activity in the protein complex. The co-chaperones of the so-called J-protein family are key, in that they "lure" the Hsp70 folding helpers to the protein aggregates and activate them precisely at their target. "The key finding of our work is that two types of these J-proteins must dynamically interact to maximally activate the Hsp70 helper proteins to dissolve the protein aggregates. Only this launches the potent cellular activity to reverse these aggregates. Now we are faced with the challenge of understanding the physiological role and the potential of the newly discovered mechanism well enough to apply these findings from basic research and develop novel strategies for therapeutic interventions."

Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation

Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology.

Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.

Comments

"On the other hand, more competition and diversity in research strategies is usually a good thing."

Yes diversity in approach is a good thing totally agree with you Reason.

I am quite interested in this proposed therapy for Parkinsons/ALS that uses H factor to help mitigate the plaque build up. I mentioned it earlier this week but it does seem like an interesting approach and unlike some of the others I have seen. Unfortunately I am not an expert so I could not comment on it's validity but it seems interesting and may translate to other related conditions.

http://www.google.com/patents/US20140234275

Posted by: Steve H at August 12th, 2015 7:06 AM

@Lou yes this one is very promising and I have been following their work. I was speaking to the UK Alzheimer's society about this therapy and they expressed an interest to fund it even if they normally do not fund outside the UK. They said they could hopefully fund the work if Neurophage could find a researcher in the UK to work with them. I passed the info to the company so hopefully they may gain some support from the UK side of the pond.

Posted by: Steve H at August 14th, 2015 9:26 AM

I would love to hear Michael Rae or Aubrey's thoughts on this therapy that seems to be compatible with SENS strategy.

I also note that it appears to clear Amyloidosis which SENS and very others identified as a problem and are working on it.

The Neurophage research data is here and their method of attacking mis-folded proteins seems to fit SENS perfectly!

http://neurophage.com/pub/01%20Krishnan_JMB_2014.pdf

Posted by: Steve H at August 15th, 2015 3:10 AM

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