Parkinson's gene may impair how new neurons are made throughout our lifetime
sheffield.ac.uk
sheffield.ac.uk
This title is rather misleading, as the neurons relevant to Parkinson's disease are generally not made at all, after birth.
>Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson’s disease (PD) is poorly understood.
(I say "not normally" because redirecting neurogenesis to supply new neurons to the substantia nigra, as a treatment for Parkinson's disease, has been an ongoing area of research for decades.)
Note also that this research study was done with zebrafish, whose neurobiology is dramatically different from humans.
"Zebrafish are a particularly valuable tool to study neurogenesis in vertebrates. Basal levels of neurogenesis occur at higher levels than in mammals, and additional proliferative zones are found throughout the brain"
In the zebrafish model, which yes, is different from the human brain, the researchers specifically demonstrate that neurogenesis is occurring in dopaminergic regions throughout life:
"... we demonstrate that ascending TPp DA neurons and local-projecting PVO neurons, but not magnocellular ascending DA neurons, are each generated into adulthood in wild type animals at a rate that decreases with age."
PINK1 deficiency slows the rate of the generation of DA neurons in zebrafish. Following this result, they then turned to the question of applicability to human systems by testing PINK1 deficiency on a culture of human midbrain organoids and successfully showed that this gene downregulated the size these organoids reached, demonstrating that this gene has an effect on neurogenesis of human dopaminergic neurons from the substantia nigra.
"Isolated observations in animal models of PD always raise concerns about the applicability of any results to human patients with this condition. However, the observation of impairment of DA neurogenesis in a PINK1-deficient, human tissue derived organoid model confirmed the initial observations."
But there is no neurogenesis of human dopaminergic neurons in the adult substantia nigra.
To create the organoid model, they used fibroblasts to generate induced pluripotent stem cells, and then differentiated these into neurons in culture. As an experimental model, this is fine, but it is not particularly indicative of actual human biology.
The most you could probably infer from this paper is that IF there were dopaminergic progenitors in the human substantia nigra (there aren't), they MIGHT respond this way if you deleted PINK1.
Two regions of the mature mammalian brain generate new neurons: (a) the border of the lateral ventricles of the brain (subventricular zone) and (b) the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. [0]
In adult humans, neural progenitors migrate from the early postnatal SVZ into neocortical and striatal areas [1].
[0] https://pubmed.ncbi.nlm.nih.gov/31568602/
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564523/
see also
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3106107/
https://translationalneurodegeneration.biomedcentral.com/art...
But there are two relevant questions: first, does this constitute orthotopic neurogenesis in any meaningful way? The progenitors are specified as interneurons in both the olfactory bulb or the dentate gyrus, certainly in the absence of any factors that encourage transition to a dopaminergic phenotype. Second, is there enough neurogenesis in the adult human brain for any purpose? Probably the most careful scientist in this space is Arturo Alvarez-Buylla, and his two Nature papers on postnatal neurogenesis in humans [0, 1] paint a fairly bleak picture.
[0]: SVZ neurogenesis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197903/
[1]: Hippocampal neurogenesis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179355/
Science is neither bleak nor joyous. Science is just a process for uncovering facts, which may or may not hint at mechanisms that may or may not yield future possibilities.
The future is not writ yet.
Exercise-Mediated Neurogenesis in the Hippocampus via BDNF
Edit: the title’s not even misleading; “Parkinson’s” modifies “gene,” not “neurons” so it’s not even saying anything about the location of these neurons or when they are being created!
For my own understanding: how can we confidently assert that this is true?
There are two main stem cell populations in the brain, which produce new neurons in two discrete regions. One stem cell population is adjacent to the substantia nigra, but produces neurons which migrate to an entirely different region of the brain (involving a "cell highway" known as the rostral migratory stream). There are experimental ways to "misdirect" these new neurons towards the substantia nigra, but there have been no durable experimental or clinical successes. Furthermore, it is relatively straightforward to look for neural stem cells in brain tissue, and to my knowledge, none have been found in the substantia nigra per se.
In spite of the efforts, it is true that finding new neurons in the brain is very challenging, if for no other reason than that there are very few of them. One fascinating study from a few years ago actually used the elevated levels of atmospheric carbon-14 during the Cold War as a label with which to identify new neurons from the second stem cell population [1]. It's now considered that they greatly overestimated the number of new neurons, but it is still a seminal paper in the field.
[0]: Good review, though somewhat technical: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659986/
However, the migration can be demand driven, in response to disease conditions.
Is Mg deficiency part of the issue? https://www.ncbi.nlm.nih.gov/books/NBK507269/#_ch17_Low_Mg_a...