[gwerbret]

They are misrepresenting the state of knowledge in that field. It has indeed been known -- since the 90s -- that there is ongoing neurogenesis in the human brain after birth. However, it is also well-known that these new neurons are produced in regions of the brain that are not relevant to Parkinson's. The specific neurons that are lost in this disease, from a region of the brain known as the substantia nigra, are not normally replaced by ongoing neurogenesis.

(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.

[phcordner]

This is also addressed in the paper:

"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."

[gwerbret]

> demonstrating that this gene has an effect on neurogenesis of human dopaminergic neurons from the substantia nigra.

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.

[wombatmobile]

> But there is no neurogenesis of human dopaminergic neurons in the adult substantia nigra.

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...

[gwerbret]

Indeed, as I wrote elsewhere. (I can't directly respond to your other comment, with which I also agree).

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/

[wombatmobile]

> his two Nature papers on postnatal neurogenesis in humans [0, 1] paint a fairly bleak picture.

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808288/

[phcordner]

In neurobiology, human in vivo studies are prohibitive from a cost, logistical, and ethical standpoint. But to anyone who can successfully parse a neurobiology paper this is assumed knowledge.

[gwerbret]

To return the goal posts to their original location, my premise was that the title "Parkinson's gene may impair how new neurons are made throughout our lifetime" is misleading, as the neurons in question are not actually made throughout our lifetimes. The referenced paper, which uses zebrafish and a somewhat contrived cell culture model, does not provide any new evidence about actual dopaminergic neurogenesis in humans. It is fair to say that if they'd actually demonstrated such neurogenesis actually occurs, with or without PINK1, the paper wouldn't have been published in just Scientific Reports.

[phcordner]

Okay man, cool. Let me know when your open-brain Dr. Mephisto trials disproving adult DA neurogenesis are written up in Nature

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!

[drewblaisdell]

> But there is no neurogenesis of human dopaminergic neurons in the adult substantia nigra.

For my own understanding: how can we confidently assert that this is true?

[gwerbret]

This has been a topic of intensive research for several decades [0]. In a nutshell, people have looked, repeatedly, and have failed to find very much.

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/

[1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394608/

[wombatmobile]

> 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).

However, the migration can be demand driven, in response to disease conditions.

https://pubmed.ncbi.nlm.nih.gov/18394605/