A 2020 study suggests that monkeys can develop Parkinson’s, just like humans. Why haven't the findings been duplicated, and what will it take to find more “natural” animal models?
Fantastic piece - really getting into some interesting corners of how we are trying to understand neurodegeneration.
Here is a section from my thesis you might find interesting:
> Do other animals get PD or other neurodegenerative diseases? In much of the literature, it is often claimed that neurodegenerative diseases are an exclusively human phenomena, and possible explanations for this have been suggested. As cited in “The Evolution-Driven Signature of Parkinson’s Disease” (Diederich et al., 2020), which will be discussed, these ideas can be drawn back to fundamental work by Parent and colleagues where it was stated that “structures that appear early in the evolution are among the first to undergo involution in ageing diseases” and “the neurodegenerative processes at play specifically target the most phylogenetically ancient components of the brain, including the SN” (Parent, 1997).
In an elegant brief communication, Paul Manger says, “The majority of neuroscience research is focused on 3 species, rat, mouse and human. The general aim is to understand the basis of human neural function and dysfunction, and to develop therapeutics or interventions; however, over 80% of potential therapeutics developed in rodent models do not translate to the human condition, i.e. these rodent models are inefficient” (P. Manger, 2019) (P. Manger, 2019). Of course, these repeated failures are perhaps merely a reflection of a fact that our knowledge of biology is far from complete, and that our attempts to test potential therapies are often too late in disease progression.
Though limited, there is a neuroscience literature in a greater diversity of species. This is useful because many of the functional and structural systems are well conserved across vertebrates, and especially mammals (Cisek, 2021; P. R. Manger, 2020; Yamamoto & Vernier, 2011). Are there examples of human (brain) diseases in other species?
Age is the greatest risk factor for cognitive decline and many neurodegenerative diseases; therefore, it is an essential variable to consider when seeking to discover human, age-associated diseases, in the wild. Mild cognitive impairment often precedes a diagnosis of dementia in humans. Interestingly, cognitive impairment has been described in one-third of dogs by age 12 and two-thirds by age 16. Furthermore, dyskinesias in dogs have been reported purportedly due to basal ganglia dysfunction. Additionally, Alzheimer’s-disease-related-pathology (Aβ plaques, neurofibrillary-related changes and cognitive deficits) have been reported in dogs, cats, dolphins, sheep, goats, wolves, polar bears, lemurs, chimpanzees, rhesus monkeys, African green monkeys, and squirrel monkeys (Devinsky et al., 2018). Interestingly, rather obscure but fascinating hypotheses have been put forward to suggest that post-reproductive life span may be a key variable in terms of age and occurrence of Alzheimer’s. Gunn-Moore and colleagues put forward the idea that the known link between failure in insulin signalling, type-2 diabetes, and Alzheimer’s may be a consequence of a long post-reproductive life span. Dolphins are animals with long post-reproductive life spans, and both tangle and plaque (Alzheimer’s) pathology have been observed in stranded animals (Gunn-Moore et al., 2018; Sarasa & Gallego, 2006). “Pathology-like”, however, is of course not human disease.
Longevity, or rather, elevated mean age — at least in the context of a post-industrialised society — seems to be uniquely human. However, data does exist — weak in nature, but existent nonetheless — showing significant longevity “in the wild”. Elephants are reported to live well up to 70–80 years (Chusyd et al., 2021), and Bowhead whales (Balaena mysticetus), for example, have been estimated to live well over 100 years consistently. Evidence even suggests that there have been individuals over 200 years old (George et al., 1999; Keane et al., 2015). Other work exists showing “AD pathology” as well as α-synuclein Lewy pathology in nine species of stranded toothed whales. The authors note, however, that they interpret these data as being potentially due to hypoxia (rather than ageing) due to the diving nature of the animals — positing the question as to which is causative (Sacchini et al., 2020). Notwithstanding, there does seem to be an absence of evidence for overt neurodegenerative diseases in the wild, rather than evidence of absence.
The core ideas that summarise why PD may be an exclusively human disease are best described in Garcia-Ruiz & Espay, 2017, Diederich et al., 2020, and Diederich et al., 2019. These ideas are elegant and well-substantiated by the data. Some of these ideas can trace their origins back to Parent’s work, suggesting that the most evolutionary conserved components of the basal ganglia — which seem to have diverged ~500 million years ago — remain relatively similar across the taxa [Cyclostomes (lamprey), Chondrichthyes (sharks), Osteichthyes (lungfish), and Tetrapods (amphibians, reptiles, birds, and mammals)], and are the most vulnerable in disorders of ageing, in particular PD (Parent, 1997). Why then might SNc DA neurons in humans be vulnerable to PD, but those in the rodent, not?
Despite such conserved network structure and physiology, mammalian brain evolution has generated great diversity. Ancestral mammalian brains were relatively small but have evolved to be highly variable in size: modern mammalian brains vary in size by 100,000-fold (Count, 1947). However, this crude measurement does little to interrogate the variation in the composition of the brain. It is suggested that the variability in mammalian brains is due to varying mechanisms of scaling. For example, the expansions of the cerebral cortex across species are not consistent with increases in brain size (Herculano-Houzel, Manger, et al., 2014). The African elephant brain is ~3 times larger than the human brain, containing ~257 billion neurons. However, ~98% of these neurons are found in an enlarged cerebellum. In contrast, their cerebral cortex has two times the mass of that found in humans, with only 5.6 billion neurons: roughly one-third of those found in humans (Herculano-Houzel, Avelino-de-Souza, et al., 2014)(though unintuitive, this is not an error). The mechanisms of scaling involve both the expansion (or reduction) of neuron numbers within specific structures, but also the variation in the size of these neurons.
It would be interesting to see Connectomics take a shot at this. If we can create a perfect neuronal mapping of the monkey's brain and can simulate parkinsons, that will lead to such fast pace of understanding. But unfortunately, mapping neuronal connect of such a large organism as a technology is possibly decades away.
Great review! But I am curious how much the comparison with TB in guinea pig holds, because of the etiological diversity in Parkinson's.
TB is more etiologically well-defined - and hence studying antibiotics in another animal infected by the bacterium helps. Is Parkinson's similar? Even from the evidence you cited, the role of multiple mutations combined with environmental effects, one wonders if Parkinson's (and some other neurodegenerative diseases like Alzheimer's) are actually a constellation of different causes that manifest in very similar phenotypic progressions, and hence get clustered as a single "disease." In that paradigm, the challenge isn't just finding one right model organism, but is it to find ones for each of those etiologies?
It's a fair question. So far, efforts to separate out treatments for Parkinson's by presumed cause haven't had success. Neither have they for other CNS diseases, as far as I know. It's possible that the analogy here would be a house fire, where a fire extinguisher works just as well for a fire caused by a candle or an electrical short. It does seem that way so far for the symptomatic Parkinson's treatments that exist (i.e. L-Dopa). So, perhaps just one model organism will suffice for the purposes we need.
But I think we'll only get a good answer once we find that one good model organism. Right now, we have zero.
Some precision from the author Hao Li (by email): "we randomly found 60 candidates for spontaneous PD of different ages without any experiments from a population of >1500 monkeys, and then we kept each of them in a single cage and observed them for a period of time, and finally we were fortunate enough to find 1 monkey with spontaneous PD"
I like the very practical (and cheap) path forward presented here. However, writing NIH grant proposals is a lot of work, and you usually want to use them as an opportunity to ask for large amounts of money, and set yourself up so you have the opportunity to ask for commensurate renewal funding down the line when the initial funding runs out. Unfortunately their isn't a lot of incentive for projects with this kind of funding structure.
Fantastic piece - really getting into some interesting corners of how we are trying to understand neurodegeneration.
Here is a section from my thesis you might find interesting:
> Do other animals get PD or other neurodegenerative diseases? In much of the literature, it is often claimed that neurodegenerative diseases are an exclusively human phenomena, and possible explanations for this have been suggested. As cited in “The Evolution-Driven Signature of Parkinson’s Disease” (Diederich et al., 2020), which will be discussed, these ideas can be drawn back to fundamental work by Parent and colleagues where it was stated that “structures that appear early in the evolution are among the first to undergo involution in ageing diseases” and “the neurodegenerative processes at play specifically target the most phylogenetically ancient components of the brain, including the SN” (Parent, 1997).
In an elegant brief communication, Paul Manger says, “The majority of neuroscience research is focused on 3 species, rat, mouse and human. The general aim is to understand the basis of human neural function and dysfunction, and to develop therapeutics or interventions; however, over 80% of potential therapeutics developed in rodent models do not translate to the human condition, i.e. these rodent models are inefficient” (P. Manger, 2019) (P. Manger, 2019). Of course, these repeated failures are perhaps merely a reflection of a fact that our knowledge of biology is far from complete, and that our attempts to test potential therapies are often too late in disease progression.
Though limited, there is a neuroscience literature in a greater diversity of species. This is useful because many of the functional and structural systems are well conserved across vertebrates, and especially mammals (Cisek, 2021; P. R. Manger, 2020; Yamamoto & Vernier, 2011). Are there examples of human (brain) diseases in other species?
Age is the greatest risk factor for cognitive decline and many neurodegenerative diseases; therefore, it is an essential variable to consider when seeking to discover human, age-associated diseases, in the wild. Mild cognitive impairment often precedes a diagnosis of dementia in humans. Interestingly, cognitive impairment has been described in one-third of dogs by age 12 and two-thirds by age 16. Furthermore, dyskinesias in dogs have been reported purportedly due to basal ganglia dysfunction. Additionally, Alzheimer’s-disease-related-pathology (Aβ plaques, neurofibrillary-related changes and cognitive deficits) have been reported in dogs, cats, dolphins, sheep, goats, wolves, polar bears, lemurs, chimpanzees, rhesus monkeys, African green monkeys, and squirrel monkeys (Devinsky et al., 2018). Interestingly, rather obscure but fascinating hypotheses have been put forward to suggest that post-reproductive life span may be a key variable in terms of age and occurrence of Alzheimer’s. Gunn-Moore and colleagues put forward the idea that the known link between failure in insulin signalling, type-2 diabetes, and Alzheimer’s may be a consequence of a long post-reproductive life span. Dolphins are animals with long post-reproductive life spans, and both tangle and plaque (Alzheimer’s) pathology have been observed in stranded animals (Gunn-Moore et al., 2018; Sarasa & Gallego, 2006). “Pathology-like”, however, is of course not human disease.
Longevity, or rather, elevated mean age — at least in the context of a post-industrialised society — seems to be uniquely human. However, data does exist — weak in nature, but existent nonetheless — showing significant longevity “in the wild”. Elephants are reported to live well up to 70–80 years (Chusyd et al., 2021), and Bowhead whales (Balaena mysticetus), for example, have been estimated to live well over 100 years consistently. Evidence even suggests that there have been individuals over 200 years old (George et al., 1999; Keane et al., 2015). Other work exists showing “AD pathology” as well as α-synuclein Lewy pathology in nine species of stranded toothed whales. The authors note, however, that they interpret these data as being potentially due to hypoxia (rather than ageing) due to the diving nature of the animals — positing the question as to which is causative (Sacchini et al., 2020). Notwithstanding, there does seem to be an absence of evidence for overt neurodegenerative diseases in the wild, rather than evidence of absence.
The core ideas that summarise why PD may be an exclusively human disease are best described in Garcia-Ruiz & Espay, 2017, Diederich et al., 2020, and Diederich et al., 2019. These ideas are elegant and well-substantiated by the data. Some of these ideas can trace their origins back to Parent’s work, suggesting that the most evolutionary conserved components of the basal ganglia — which seem to have diverged ~500 million years ago — remain relatively similar across the taxa [Cyclostomes (lamprey), Chondrichthyes (sharks), Osteichthyes (lungfish), and Tetrapods (amphibians, reptiles, birds, and mammals)], and are the most vulnerable in disorders of ageing, in particular PD (Parent, 1997). Why then might SNc DA neurons in humans be vulnerable to PD, but those in the rodent, not?
Despite such conserved network structure and physiology, mammalian brain evolution has generated great diversity. Ancestral mammalian brains were relatively small but have evolved to be highly variable in size: modern mammalian brains vary in size by 100,000-fold (Count, 1947). However, this crude measurement does little to interrogate the variation in the composition of the brain. It is suggested that the variability in mammalian brains is due to varying mechanisms of scaling. For example, the expansions of the cerebral cortex across species are not consistent with increases in brain size (Herculano-Houzel, Manger, et al., 2014). The African elephant brain is ~3 times larger than the human brain, containing ~257 billion neurons. However, ~98% of these neurons are found in an enlarged cerebellum. In contrast, their cerebral cortex has two times the mass of that found in humans, with only 5.6 billion neurons: roughly one-third of those found in humans (Herculano-Houzel, Avelino-de-Souza, et al., 2014)(though unintuitive, this is not an error). The mechanisms of scaling involve both the expansion (or reduction) of neuron numbers within specific structures, but also the variation in the size of these neurons.
"Interestingly, cognitive impairment has been described in one-third of dogs by age 12 and two-thirds by age 16"
Was not aware of this fact. Thanks for this comment!
It would be interesting to see Connectomics take a shot at this. If we can create a perfect neuronal mapping of the monkey's brain and can simulate parkinsons, that will lead to such fast pace of understanding. But unfortunately, mapping neuronal connect of such a large organism as a technology is possibly decades away.
https://www.asimov.press/p/barcoding-brains
Great review! But I am curious how much the comparison with TB in guinea pig holds, because of the etiological diversity in Parkinson's.
TB is more etiologically well-defined - and hence studying antibiotics in another animal infected by the bacterium helps. Is Parkinson's similar? Even from the evidence you cited, the role of multiple mutations combined with environmental effects, one wonders if Parkinson's (and some other neurodegenerative diseases like Alzheimer's) are actually a constellation of different causes that manifest in very similar phenotypic progressions, and hence get clustered as a single "disease." In that paradigm, the challenge isn't just finding one right model organism, but is it to find ones for each of those etiologies?
It's a fair question. So far, efforts to separate out treatments for Parkinson's by presumed cause haven't had success. Neither have they for other CNS diseases, as far as I know. It's possible that the analogy here would be a house fire, where a fire extinguisher works just as well for a fire caused by a candle or an electrical short. It does seem that way so far for the symptomatic Parkinson's treatments that exist (i.e. L-Dopa). So, perhaps just one model organism will suffice for the purposes we need.
But I think we'll only get a good answer once we find that one good model organism. Right now, we have zero.
Some precision from the author Hao Li (by email): "we randomly found 60 candidates for spontaneous PD of different ages without any experiments from a population of >1500 monkeys, and then we kept each of them in a single cage and observed them for a period of time, and finally we were fortunate enough to find 1 monkey with spontaneous PD"
I like the very practical (and cheap) path forward presented here. However, writing NIH grant proposals is a lot of work, and you usually want to use them as an opportunity to ask for large amounts of money, and set yourself up so you have the opportunity to ask for commensurate renewal funding down the line when the initial funding runs out. Unfortunately their isn't a lot of incentive for projects with this kind of funding structure.
Saw emails from asimov and you with the same title and thought I was going loopy for a sec... great piece!