Parkinson’s disease. II. The beginnings of an answer?

In a recent article (see On Parkinson’s, paraquat, and probability), I discussed Parkinson’s disease (PD). My focus was on a recent claim by a respected reporter, Nicholas Kristof, that argued that increasing use of the pesticide paraquat might be responsible for the increasing incidence of PD cases. I argued that while paraquat and other herbicides might, and indeed probably do, trigger development of PD, it was unlikely that they were solely responsible for the increasing number of cases. Kristof’s article also left untouched the pathological mechanism of PD. If PD is to be vanquished, we need to understand its pathology a lot better than we do.

Obviously, we do not have the answer to that but I wanted to end the article with something interesting, I finished therefore with a brief comment on the fact that for the two biggest causes of neurodegeneration, PD and Alzheimer’s (for the latter, see The terrible tangle of Alzheimer’s disease) both involved protein aggregation leading to neuronal death – though the proteins in the two conditions are different. Might that similarity not be a clue to the pathology?

After posting that article, I found, to my satisfaction, that there is indeed growing evidence along those lines. In this article, I will focus on a fairly new idea about PD that seems very promising, and, at the end, bring the discussion back to neurodegeneration more generally.

The best point to begin a discussion of PD is that, as mentioned in the earlier piece, about 90% of the cases are idiopathic, that is they take place in individuals without a family history of the disease. The remaining 10% seem to have had some hereditary predisposition to the illness, and indeed a few specific genes have been implicated as risk factors (see Risk factors: an introduction). However, the great majority of cases are one-off instances, without any indication of a hereditary potentiation.

That, in turn, suggests that the great majority of PD cases start with something from outside the bodies of those who come down with the disease, namely an environmental cause. Indeed, many of the known risk factors are substances that enter the body by breathing or by being swallowed. In other words, there might be two major entry-points, the nose and the mouth, by which potentially PD-inducing substances are taken in.

This idea was more than just an a priori assumption, however. Evidence for there being two entry routes – the nose and the stomach – for substances that cause PD has been building for more than 20 years. That possibility, however, suggests that there might be two different ways in which the pathology develops. Recall that the defining characteristic of PD is a small set of frequently shared defects in body movements, so called motor problems, in particular tremors of the hands (sometimes the feet as well) and difficulties in movement (the latter sometimes extreme, where voluntary movements become impossible.) However, there is also a whole range of other symptoms, ranging from gut disturbances to skin problems to sleep disorders, and PD sufferers can differ greatly as to which symptoms are experienced and when they appear relative to the motor problems. Might the idea of two different entry-points for substances that trigger the start of PD development help explain this great diversity of symptoms and times at which they occur?

This idea was developed and first published in 2019 by a Danish scientist, Per Borghammer, and his associates. They initially called their idea the “brain-first vs body-first” explanation of PD. Central to the idea was the idea that PD pathology involves aggregation of a neuronal protein, alpha-synuclein, abbreviated “asyn”, a state that spreads in the neural system, starting from the two different body entry points of the initiating substances. These aggregates spread within the nervous system via different routes and give rise to the neuronal death patterns and pathologies characteristic of PD.

Asyn, in its normal, non-aggregated state, is a protein involved in neurotransmitter release and, as might be expected from that fact, found in neuronal cells at so called pre-synaptic sites, where neurotransmitters are released. In the human body, asyn is a common protein in neurons, making up about 1% of the total protein mass of neurons. In its aggregated state, it almost certainly loses its normal function and creates a pathological state. When extensively aggregated, it creates so called Lewy bodies, which are seen in many neurodegenerative conditions, diagnostically in PD, in the nervous system sites that typically feature in the diseases.

An essential shared element of neurodegenerative diseases is that the spread of the pathology is based on something physical that spreads between connected neurons. In the terminology of neurobiology, a complete map of the nervous system connections is termed the “connectome”. In the model of Borghammer and colleagues, the pathology of PD is spread between different loci by aggregates of asyn, probably oligomers. These ideas are embodied in the second name that has been given for the brain-first vs body-first model. This is “the alpha Synuclein Origen site and Connectome model” or SOC.¹

In the model, the proposed entry point in body-first cases of PD is the part of the peripheral nervous system (PNS) that regulates the gut, the so called enteric nervous system or ENS. In the scheme, substances with PD-inducing potential that go into the stomach enter neuronal cells of the ENS, where they trigger the first events of asyn aggregation, to form small aggregates, oligomers. Those oligomers can then be transmitted to other elements of the PNS and make their way to the head where they stimulate further aggregation of the protein, producing Lewy bodies, in sites such as the substantia nigra, whose pathology is linked to the major symptoms characteristic of PD. A key neural element in that transmission from the ENS to the brain is probably the vagal nerve. This is one of the cranial nerves – it is designated the 10^th cranial nerve– that are responsible for so much of the neural messaging between the brain and the body. The vagal nerve is particularly important in this communication but may well also function, in this case harmfully, as the highway for transmitting asyn aggregates from the gut.

In contrast, in the brain-first pathway, harmful substances, such as herbicides or dry-cleaning fluids, are inhaled, entering the nasal passage and get transmitted to PNS neurons in the olfactory epithelium. There they induce asyn aggregates, and these can be transmitted to other sites in the brain, including the amygdala and the substantia nigra, which can then travel via the PNS to sites in the body affecting the nerves of the so called autonomic nervous system, which regulates the internal organs such as the heart, lungs, and gut.

How, one might ask, are the asyn aggregates transmitted between neurons? Neurons are famously connected electrically, involving so called action potentials and neurotransmitters released by the action potentials, acting between a presynaptic neuron and a postsynaptic neuron. This mode of intercellular communication, however, does not transmit molecules such as protein aggregates between neurons. Ions and small molecules can be transferred via small channels called gap junctions but those are too small for the kind of protein molecules believed to be transferred in neurodegenerative diseases.

There are, however, larger channels between neighboring neurons that might be involved. These are termed “tunneling nanotubes or TNTs”. These are large enough to transmit small asyn aggregates, oligomers. Whether they actually do so is unknown at present but this can be tested experimentally and the issue resolved.

Another possible means of cell-to-cell transfer could be via the small membrane vesicles termed exosomes, which can be budded off from cell membranes, including those of neurons, and then fuse with other cells. This mechanism may have evolved to help cells get rid of such molecules as protein aggregates, which are harmful to the cell. However, exosomes have the capability of fusing with the membranes of other cells, and if so, they might carry and transmit molecules such as asyn aggregates. They have been shown to be capable of transporting aggregates of alpha beta amyloid protein in Alzheimer’s disease and probably are, in that way, a key element in spreading the pathology of that condition amongst neurons in the brains of people undergoing that disease.²

The SOC hypothesis is still only just that, a hypothesis, an unproven idea. It seems a very good one to me, explaining the diversity of symptoms and the different varieties of PD and it is consistent with the broadly known facts about asyn aggregation and its spread within the nervous system. Is it actually true, however? Fortunately, it makes some clear predictions about the patterns in which symptoms appear in different individuals, the rough time course of that appearance, and, not least, that it predicts roughly the existence of two major kinds of PD with respect to symptoms, time course, and spatial pattern. One such prediction is that for cases of PD that seemed to start with various non-motor problems, such as heart beat irregularities, gut problems, sleep disturbances – the body-first pattern – the time course of illness leading to and including the motor problems, should be longer than the presumed brain-first cases.

Furthermore, these predictions have been tested by a number of research groups, not just the original proposers, and by and large, the predictions have been fulfilled. There are complications and not everything fits the picture drawn in the original proposals but it is a fairly good match. Remember that there are other risk factors that almost certainly come into play in various cases of PD and those could well affect the pattern of appearance of and timing of the symptoms.³

An additional attractive feature is that the idea poses new challenges to the scientific analysis of PD pathology, such as better detection methods for asyn aggregates. The further development of those approaches should further help the development of this research area beyond new tests of the SOC itself.

Finally, we come back to the phenomenon of protein aggregation and the questions it raises. It has been implicated as a factor in other neurodegenerative diseases beyond Alzheimer’s disease. Why should this be the case? In other words, why should this be a shared phenomenon even when different proteins are involved and when this is so clearly an undesirable biological property? Is protein aggregation simply something that happens to many proteins as people reach old age, thus just an inevitable but accidental aspect of ageing? If so, there would be little effective natural selection against it since natural selection cannot weed out biological properties that occur after reproductive life is over. Or, does such protein aggregation, at least in small amounts, serve some positive biological function? The world of neurodegenerative diseases is not only an important and interesting one in terms of human health but clearly poses a wealth of issues – in basic biology, physiology and evolution – that are intriguing and significant to biologists.

1. For the first statement of this hypothesis, which gives the relevant background information, see Borghammer, P. and N. Van Den Berghe (2019) Brain-first versus gut-first Parkinson’s disease: a hypothesis. Journal of Parkinson’s Disease 9: S281-S295. Doi. 10.3233/JPD-191721.

2. For information on this process, see Sinha, M.S. et al. (2018). Alzheimer’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathologica 136:41-56.

3. For recent discussions of the evidence relevant to the SOC hypothesis, see: 1) Horsager, J., Borghammer, P. (2024). Brain-first vs. body-first Parkinson’s disease: an update on recent evidence. Parkinsonism and Related Disorders 122.106101. doi.org/10.1016/j.parkreldis.2024.106101. 2) Borghammer, P. et al. (2021). Neuropathological evidence of body-first vs brain-first Lewy body disease. Neurobiology of Disease 161:105557. Doi.org/10.1016/j.nbd.2021.105557 3) Dorsey, E.R. et al. (2024). The body, the brain, the environment, and Parkinson’s disease. J. Parkinson’s Disease 14: 363-381. Doi.org/10.3233/JPD.240019.