Distinctly human: Kangaroos

 

It is often said that only humans develop Parkinson’s. It is a distinctly human condiiton, and this is true (at the time of publishing this post).

But there are interesting Parkinson’s-related observations in the animal world that could tell us something about this ‘very human’ condition. We have previously highlighted reports of this nature (Click here for an example).

Recently Australian researchers have reported the accumulation of the Parkinson’s-associated protein alpha synuclein in the brains of kangaroos, after they ate a particular type of grass (phalaris pastures plants) which is toxic for them.

In today’s (short) post, we will discuss what the report found, look at what the plants contains, and consider what this could mean for our understanding of Parkinson’s.

 


Source: SanDiegoZoo

The first interesting fact about kangaroos in today’s post: They are predominantly left handed

What?!?!?

Researchers published a study in 2015 reporting that while most four legged marsupials show no preference between their limbs, kangaroos are very left handedness (Click here to read the report)

Source: Cell

This finding is interesting as it could tell use much about our own handedness preference (Click here to read more about this).

Ok, interesting. But what on Earth does this have to do with Parkinson’s?

Ah, well that’s where we come to the second interesting fact about kangaroos in today’s post:

Very recently this research report was published:

Title: Plant poisoning leads to alpha-synucleinopathy and neuromelanopathy in kangaroos.
Authors: Tayebi M, El-Hage CM, Pinczowski P, Whiteley P, David M, Li QX, Varghese S, Mikhael M, Habiba U, Harman D, Tatarczuch L, Bogeski M, Birchall I, Ferguson K, Walker L, Masters C, Summers BA.
Journal: Sci Rep. 2019 Nov 13;9(1):16546.
PMID: 31723225                     (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers were investigating the “clinical and neuropathological changes associated with spontaneous cases of Phalaris staggers in kangaroos“.

Huh? What is Phalaris staggers?

Phalaris (often called ‘canary grass’) is a tall perennial grass that has large seed heads. It was introduced to southeastern Australia as a pasture crop.

Phalaris. Source: Omnilexica

It was historically popular with farmers as it was drought tolerant and has an extensive root system that can be used to stabilise water courses and gullies.

Phalaris staggers is a neurological condition that affects kangaroos when they eat tryptamine-alkaloid-rich phalaris pastures plants. “Staggers” is characterised by issues with gait and locomotion in affected animals and it can be subdivided into either an acute reversible form or (more commonly) a lethal chronic form (which is called “Phalaris staggers”).

It has been most well studied in sheep, who initially display subtle neurological features during the first three weeks of onset, but they progressively become more pronounced over the next three to four months. Farmers can manage the condition by introducing copper into the diet of their animals, and shifting them away from phalaris areas.

But for wild animals (like kangaroos) this is not an option.

What did you mean by “tryptamine-alkaloid-rich phalaris pastures plants”?

It has been suggested that Phalaris staggers is caused by chemicals called ‘tryptamine alkaloids’ which are found in high levels in Phalaris species.

Curiously, these alkaloids are structurally similar to the neurotransmitter serotonin (a neurotransmitter is a chemical in the brain that passes messages from one neuron to the next – dopamine is also a neurotransmitter). Because of this similarity, these alkaloids can act as serotonergic receptor agonists – meaning that they bind to and activate serotonin receptors.

The competitve binding to the serotonin receptor leads to a build up of excess serotonin in the brain, causing enhanced response to excitatory inputs – which in turn results in the neurological symptoms mentioned above (and in the next section below).

And long term this situation is toxic, resulting in brain damage and death.

Ok, so what did the researchers find in their study?

When the researchers observed affected kangaroos, they noted physical symptoms such as “ataxia, head shaking, erratic hopping and generalized muscle tremors“. When startled, the kangaroos exhibited episodes of excessive hyperexcitability (this is the “enhanced response to excitatory inputs” mentioned above).

But it was when the investigators looked at the brains of some of the kangaroos that passed away from the condition that they found something really interesting:

Firstly, they observed extensive accumulation of neuromelanin

What is neuromelanin?

Neuromelanin is the brain-version of a pigment called melanin, which is found in the skin, eyes, and hair. It is the substance that gives skin & eyes their colour. Dark-skinned people have more melanin in their skin than light-skinned people.

In the brain, certain types of cells, such as the dopamine neurons, produce neuromelanin.

subnigmicro

Neuromelanin (the brown patches) in dopamine neurons. Source: Schatz

Neuromelanin appears in large quantities in the human brain, in much lesser amounts in some of the non-human primates, and is almost absent from the brain in many lower species (like mice and rats).

And dopamine neurons in the human brain produce so much neuromelanin that you can visualise it with your bare eye. As you can see in the image below, the Parkinsonian brain has less dark pigmented cells (in the substantia nigra region of the midbrain). As dopamine neurons – which are affected in Parkinson’s – are lost, so too is the dark pigment of neuromelanin.

The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian brain (right). Source:Memorangapp

The neurons in certain regions of the brains of the Phalaris staggers affected kangaroos were full of neuromelanin, while the brains of unaffected kangaroos had little or no neuromelanin.

Interestingly, the researchers also looked at the nerves surrounding the intestinal system of the kangaroos and they found that they also contained melanin-like granules.

Curious. What else did the researchers find?

The second major observation that the researchers made was that the brains of the Phalaris staggers affected kangaroos also displayed an accumulation of alpha synuclein protein.

Remind me one more time what is alpha synuclein?

Alpha synuclein sounds like a distant galaxy, but it is one of the most common proteins in our brains. It makes up about 1% of all the protein in a neuron. When alpha synuclein protein is produced by a cell, it normally referred as a ‘natively unfolded protein’, in that is does not really have a defined structure.

When it is first produced, alpha synuclein will look something like this:

Alfa-sinucleina

Alpha synuclein. Source: Wikipedia

In this form, alpha synuclein is considered a monomer – which is a single molecule that can bind to other molecules. When it does bind to other alpha synuclein proteins, they form an oligomer (a collection of a certain number of monomers in a specific structure). It is believed that alpha synuclein has certain functions as a monomer, but may also have specific tasks as an oligomer.

In Parkinson’s, alpha synuclein will also misfold and aggregate together to form amyloid fibrils.

as-oligos

Microscopic images of monomers, oligomers and fibrils. Source: Brain

And it is believed that the oligomer and fibril forms of alpha synuclein protein that aggregate together, and then go on to form what we call Lewy bodies.

Parkinson’s associated alpha synuclein. Source: Nature

A Lewy body is referred to as a cellular inclusion, as they are almost always found inside the cell body. They are a characterisitic feature of the Parkinsonian brain.

A photo of a Lewy body inside of a neuron. Source: Neuropathology-web

So the researchers saw an accumulation of alpha synuclein in the brains of the kangaroos, similar to Parkinson’s?

Yes, but importantly in the brains of the Phalaris staggers affected kangaroos no Lewy body inclusions were observed.

In addition, alpha synuclein was not restricted in the affected kangaroos to the substantia nigra region, rather it was widely distributed across several areas of the brain and spinal cord. The alpha synuclein was present in mainly morphologically normal looking neurons, and it was closely associated with accumulated neuromelanin.

When the investigators compared levels of alpha synuclein in the blood of the kangaroos, they found that it was lower in Phalaris-affected kangaroos when compared with blood from unaffected kangaroos.

So what does it all mean?

Australian researchers have observed accumulation of Parkinson’s-associated alpha synuclein and neuromelanin in the brains of kangaroos that have eaten a plant that is toxic for them. The researchers were quick to point out that they “failed to demonstrate the presence of typical neuropathologic changes associated with Parkinson’s disease, namely Lewy bodies and Lewy neurites“, but they did speculate that this was “probably reflecting an acute onset“.

Given that the accumulation of alpha synuclein is so rare in the animal kingdom (to our knowledge), this observation is particularly intriguing – especially as it appears to be the result of ingesting a toxic plant. Whether this can tell us something about Parkinson’s as a condition can be debated, but probably needs to be further explored. But it is an intriguing finding.

One which brings into question how distinctly human Parkinson’s really is.

 

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The banner for today’s post was sourced from Smithsonianmag

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