S O U R C E : Life Extension Advocacy Foundation
Today, we want to point out a new publication that recently appeared in the Science Translational Medicine journal, as its authors have discovered a new mechanism by which the brain protects itself from the harmful α-synuclein protein aggregates associated with Parkinson’s and that may open the door to new therapies against these conditions.
To understand where these harmful protein aggregates come from, we should take a look at how proteins are created and what goes wrong during the process of proteostasis.
It all starts with the loss of proteostasis
Proteostasis comes from a fusion of the words ‘protein’ (a molecule that a cell uses as a machine or scaffolding) and ‘stasis’ (meaning to keep the same). The body tries to keep the production of proteins stable and without any defects; this ideal state is known as proteostasis, a balanced state in which the protein-producing machinery works perfectly.
The proteostasis network is responsible for constructing proteins through a multi-step process, the end result of which is that the desired protein performs the required function within the cell.
Proteins are large, complex molecules that regulate almost everything in your body, either directly or indirectly. They do the majority of the work in cells and are critical for the function, regulation, and structure of tissues and organs.
Proteostasis is maintained by the proteostasis network, a network that is, itself, made up largely of proteins. The proteostasis network attempts to maintain protein production without errors, and it consists of the following elements:
Ribosomes
Translates RNA into proteins. This occurs slowly enough to allow secondary structures to form as this change takes place.
Chaperones
Guides polypeptides into the correct tertiary and quaternary structures. These include the heat shock proteins, which help other proteins maintain their shape during stress, such as low oxygen, low pH, or extreme heat. This category also includes the co-chaperone molecules, which do not interact directly with the target protein but assist the chaperone to guide the target protein into the correct structural form.
Protein degradation machinery
Lysosomes are membrane-wrapped pockets of digestive enzymes that digest and recycle unwanted proteins. Ubiquitin is a medium-sized polypeptide that can be attached to any protein to mark it for regulatory action. Ubiquitin molecules are added to proteins via a series of enzymes, the last of which is tailored to the specific protein. Adding a chain of ubiquitins marks a protein for degradation via the proteasome, a large protein complex that, like lysosomes, can break down proteins into their constituent amino acids.
Unfortunately, the proteostasis network is not perfect, and, sometimes, it fails; when this happens, it can result in too few or too many proteins. It can even lead to misfolded proteins that are bent out of shape and cannot perform their jobs or cause aberrant behavior in the cell by giving the wrong instructions.
These errors in the protein production system accumulate over time, and this is why the loss of proteostasis in cells is a proposed reason why we age.
Over time, these misfolded proteins accumulate and form aggregates, which are clumps of the same or similar proteins bonded to each other. These aggregates play a key role in age-related diseases, such as Alzheimer’s and Parkinson’s, in which they destroy neurons.
α-Synuclein Aggregates
The commonly associated aggregate linked to Parkinson’s disease is α-synuclein, which plays a central role in the progression of the disease. This aggregate can travel freely between nerve cells, allowing the disease to spread. In a new study, a team of scientists has published the discovery of a mechanism that allows the body to remove this aggregate [1].
In order for the brain to function properly, non-aggregated α-synuclein proteins are needed in order to facilitate the release of dopamine, a neurotransmitter, in nerve cell synapses. α-synuclein only becomes a problem when proteostasis fails and the proteins misfold, aggregate, and accumulate.
During disease progression, α-synuclein aggregates form into long microscopic fibers, or fibrils, which prevent nerve cells from functioning correctly. These fibrils are harmful to nerve cells and ultimately cause the dopamine-producing cells to die, leaving the brain starved of dopamine, causing the shakes and muscle tremors typically observed in Parkinson’s disease.
During the study, the researchers showed that the α-synuclein fibrils are able to enter and infect nearby healthy nerve cells. Once they enter the new cells, they recruit more α-synuclein molecules to the aggregated mass, causing the previously non-aggregated α-synuclein to misfold and join the aggregate too. This is how the disease appears to spread and steadily infect entire brain regions.
The research team also discovered that there is a cellular mechanism that helps to break down α-synuclein fibrils, a protein complex known as SCF. This is a previously unknown contributor to the proteostasis network, and it targets α-synuclein fibrils with ubiquitin and prepares it for degradation via the proteasome, which is part of the waste disposal machinery of the proteostasis network.
When they tested this in mice by blocking the function of the SCF complex, the α-synuclein fibrils were no longer removed, beginning to accumulate in the nerve cells and spread through the mouse brain. They also found that the more active the SCF complex is in the brain, the faster α-synuclein fibrils are cleared, which means that the complex could slow down or even completely stop the progression of Parkinson’s if present in large enough amounts.
Unfortunately, the SCF complex is very short-lived and normally dissipates within a matter of minutes; the next logical step for the researchers is to create a much more stable form of the complex so that it remains present for longer periods of time. If SCF can be made to be much more persistent, it would mean it could combat α-synuclein fibrils for greater periods of time, potentially halting the disease.
It also opens the door for transplanting fresh nerve cells into the brains of Parkinson’s patients, a strategy that has failed in the past, as any healthy cells transplanted to the brain are rapidly infected by the α-synuclein fibrils. The potential here is obvious: it may be possible to not only use SCF to clear out the α-synuclein fibrils and halt the disease but to also reverse it by using transplants to replace what was lost.
Finally, the researchers have raised the prospect of modifying stem cells so that their SCF activity is higher than normal, meaning that transplanted cells would be much more resistant to α-synuclein fibrils and would clear down aggregates more efficiently than regular nerve cells do.
Parkinson’s disease (PD) is a neurological disorder characterized by the progressive accumulation of neuronal α-synuclein (αSyn) inclusions called Lewy bodies. It is believed that Lewy bodies spread throughout the nervous system due to the cell-to-cell propagation of αSyn via cycles of secretion and uptake. Here, we investigated the internalization and intracellular accumulation of exogenous αSyn, two key steps of Lewy body pathogenesis, amplification and spreading. We found that stable αSyn fibrils substantially accumulate in different cell lines upon internalization, whereas αSyn monomers, oligomers, and dissociable fibrils do not. Our data indicate that the uptake-mediated accumulation of αSyn in a human-derived neuroblastoma cell line triggered an adaptive response that involved proteins linked to ubiquitin ligases of the S-phase kinase-associated protein 1 (SKP1), cullin-1 (Cul1), and F-box domain–containing protein (SCF) family. We found that SKP1, Cul1, and the F-box/LRR repeat protein 5 (FBXL5) colocalized and physically interacted with internalized αSyn in cultured cells. Moreover, the SCF containing the F-box protein FBXL5 (SCFFBXL5) catalyzed αSyn ubiquitination in reconstitution experiments in vitro using recombinant proteins and in cultured cells. In the human brain, SKP1 and Cul1 were recruited into Lewy bodies from brainstem and neocortex of patients with PD and related neurological disorders. In both transgenic and nontransgenic mice, intracerebral administration of exogenous αSyn fibrils triggered a Lewy body–like pathology, which was amplified by SKP1 or FBXL5 loss of function. Our data thus indicate that SCFFXBL5 regulates αSyn in vivo and that SCF ligases may constitute targets for the treatment of PD and other α-synucleinopathies.
Conclusion
This is a fascinating discovery that, if it translates to humans, has the potential to be transformative. As there is a natural mechanism to remove α-synuclein fibrils, finding ways to boost and utilize this natural system is the obvious next step towards developing effective therapies.
Engineering resilience is the logical progression towards making us increasingly resistant to age-related diseases. We wish the researchers every success in developing effective therapies for Parkinson’s disease, and we will be following their progress closely.
