Study clarifies how spermine can guard against Alzheimer’s and Parkinson’s

Researchers at the Paul Scherrer Institute PSI have clarified how spermine - a small molecule that regulates many processes in the body's cells - can guard against diseases such as Alzheimer's and Parkinson's: it renders certain proteins harmless by acting a bit like cheese on noodles, making them clump together. This discovery could help combat such diseases. The study has now been published in the journal Nature Communications. 

Our life expectancy keeps rising - and as it does, age-related illnesses, including neurodegenerative diseases such as Alzheimer's and Parkinson's, become increasingly common. These diseases are caused by accumulations in the brain of harmful protein structures consisting of incorrectly folded amyloid proteins. Their shape is reminiscent of fibres or spaghetti. To date, there is no effective therapy to prevent or eliminate such accumulations.

Yet a naturally occurring molecule in the body called spermine offers hope. In experiments, researchers led by study leader Jinghui Luo, in the Center for Life Sciences at the Paul Scherrer Institute PSI, have discovered that this substance is capable of extending the life span of small nematode worms, improving their mobility in old age, and strengthening the powerhouses of their cells - the mitochondria. Specifically, the researchers observed how spermine helps the body's immune system eliminate nerve-damaging accumulations of amyloid proteins.

The new findings could serve as a basis for developing novel therapies for such diseases.

A central mediator of cellular processes

Spermine is a vital substance for the organism. It belongs to the so-called polyamines, which are relatively small organic molecules. Spermine, first discovered more than 150 years ago, is named after the seminal fluid, as it is found in particularly high concentrations there. But it also occurs in many other cells of the body - especially those that are active and capable of dividing.

Spermine promotes cell mobility and activity and controls numerous processes. Above all, it interacts with the nucleic acids of the genome, regulating the expression of genes and their conversion into proteins. This ensures that cells can properly grow and divide and ultimately die. Spermine is also central to an important cellular process called biomolecular condensation: In this process, certain macromolecules, such as proteins and nucleic acids, segregate and collect within the cell in a droplet-like form, so that important reactions can take place there.

In connection with neurodegenerative diseases such as Alzheimer's or Parkinson's, there has previously been evidence that spermine can protect nerve cells and alleviate age-related memory loss. Lacking until now, however, has been a more precise understanding of how spermine intervenes in nerve-damaging processes - understanding that might make it possible to derive medical benefits from it.

Assisting cellular waste removal

Jinghui Luo's group has now investigated this in more detail. In addition to optical microscopy, the researchers also used the SAXS scattering technique at PSI's Swiss Light Source SLS to shed light on the molecular dynamics of these processes. The investigations were conducted both in a glass capillary (in vitro) and in a living organism (in vivo). The nematode C. elegans served as a model organism.

It was shown that spermine causes the harmful proteins to gather and, in a sense, clump together through biomolecular condensation. This facilitates a process called autophagy, which occurs routinely in our cells: Damaged or unnecessary proteins are wrapped up in small membrane vesicles and safely degraded with enzymes - a natural recycling process, in effect.

Autophagy is more effective at handling larger protein clumps. And spermine is, so to speak, the binding agent that brings the strands together. There are only weakly attractive electrical forces between the molecules, and these organise them but do not firmly bind them together."

Jinghui Luo, study leader 

The whole thing, says Luo, can also be imagined like a plate of spaghetti. "The spermine is like cheese that connects the long, thin noodles without gluing them together, making them easier to digest."

Wanted: the right combination of ingredients

Spermine also exerts an influence on other diseases, including cancer for example. Here too research is needed to clarify the mechanisms at work - then spermine-based therapeutic approaches would be conceivable. In addition to spermine, there are many other polyamines that fulfil important functions in the organism and thus are medically interesting. Therefore research in this area has a lot of potential. "If we better understand the underlying processes," says Luo, "we can cook tastier and more digestible dishes, so to speak, because then we'll know exactly which spices, in which amounts, make the sauce especially tasty."

Artificial intelligence is also being used in this search, because it can calculate promising combinations of "ingredients for the sauce" much more quickly on the basis of all available data. Luo also notes that time-resolved scattering measurement techniques and high-resolution imaging, which can depict such processes in real time and down to the subcellular level, are also important for this and subsequent studies. Apart from PSI, such methods are available at only a few other synchrotron facilities in the world.