Cumulative DNA damage in active vs. less active neurons?

[asimov42]

TL;DR Summary

Looking for a recent study.

Hi all,

In light of recent findings about Topoisomerase-mediated DNA double strand breaks, I have been looking for a study out there that compares cummulative DNA damage in active neurons vs. less active counterparts. So far I have not been able to find anything - this would hopefully be over a period of time.

Does anyone know if such a study or similar studies have been done recently?

Thanks.

 

[jedishrfu]

So are more active neurons reproduced more than less active neurons?

perhaps if you knew the rate of cell production then you could determine the rate of DNA damage?

 

[jim mcnamara]

I had a look at papers using Google Scholar, the most recent one I found is dated 2012.

What is your idea of recent? Could you please cite one of these recent works? So we are all talking about the same thing.

 

[asimov42]

Hi jim,

Thanks - yes, here's one:

Topoisomerases and the regulation of neural function
Nat Rev Neurosci. 2016 Nov; 17(11): 673–679.
Published online 2016 Sep 15. doi: 10.1038/nrn.2016.101

Specifically, I am hoping to find something related to the review article:

A Shortcut to Activity-Dependent Transcription
Cell
Volume 161, Issue 7, 18 June 2015, Pages 1496-1498

"One might note that the repeated formation of DSB followed by NHEJ at activity-dependent loci appears to be a risky strategy for a neuron. If DSBs form at activity-induced genes each time the neuron is activated, over the course of the life of an organism, even a low error rate in the repair process would lead to a significant mutational load. When combined with the previous finding that there is an increase gamma-H2AX phosphorylation in vivo as a consequence of sensory experience (Suberbielle et al., 2013), the results of Madabhushi et al. raise the possibility that a negative consequence of the normal activation of neurons may be a high rate of mutation at activity-induced genes... Future studies examining if extensive mutagenesis occurs specifically at regulatory regions of activity-dependent genes in the aging brain will help to test this prediction."

Looking for any study related to the last sentence. Would be nice to determine if normal neural activity led to greater DNA damage.

 

[BillTre]

Almost all neurons are terminally differentiated and not able to under go cell division. The common thought is that they are too structurally specialized to divide without losing a lot of their cellular specializations.

If the cells don't divide, a set of possible problems from DNA damage (double strand DNA beaks) would not be noticed. During cell division, unrepaired double strand breaks can result in the severed bits of chromosomes being lost since they are no longer connected to their centromeres (attachment points to the microtubule based mitotic spindle) and are not efficiently moved into the new nuclei of the new daughter cells.

 

[Ygggdrasil]

I'm not familiar enough with this area to know if there are studies that address your particular question, but I do know that there has been interest in studying how DNA damage and other mutational processes can cause individual neurons to differ at the genetic level. For example, see this review from 2017:

Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network
https://science.sciencemag.org/content/356/6336/eaal1641

Popular press summary: https://www.scientificamerican.com/...to-find-no-two-neurons-are-genetically-alike/

Search for papers about somatic mosaicism in neurons for more studies.

 

[asimov42]

If the cells don't divide, a set of possible problems from DNA damage (double strand DNA beaks) would not be noticed. During cell division, unrepaired double strand breaks can result in the severed bits of chromosomes being lost since they are no longer connected to their centromeres (attachment points to the microtubule based mitotic spindle) and are not efficiently moved into the new nuclei of the new daughter cells.

But if you have a DSB in any neuron at an active transcription site, the risk of a mutation there will affect transcription - thus mutations resulting from incorrectly repaired DSB have a major impact in e.g., Alzheimer's, etc., no?

 

[BillTre]

But if you have a DSB in any neuron at an active transcription site, the risk of a mutation there will affect transcription - thus mutations resulting from incorrectly repaired DSB have a major impact in e.g., Alzheimer's, etc., no?

True.
A DSB could break a gene and mess up its transcripts or control mechanisms.
This would only affect one copy of the cell's two copies. This might or might not be a problem depending upon the particulars of the situation.

 

[asimov42]

Actually I would really just like to find a study that compares the genomic damage and mutations in an active (highly simulated) population of neurons with those less active, to compare the effect that neural activity has on DNA.

The last sentence from the Cell article that I quoted, "Future studies examining if extensive mutagenesis occurs specifically at regulatory regions of activity-dependent genes in the aging brain will help to test this prediction," is really what I'm after, and since it's been five years I'm sure someone must have done something.

There is dichotomy here between what's typically been the (supported by a number for papers) orthodox view - neural activity is beneficial to survival in post-mitotic neurons (and the reason we're all told to "keep our brains active!" as we age) and the above finding that everyday transcriptional activity induces DSBs that might lead to mutations.

Looking for any resource that clarifies this. Thanks all.

 

[BillTre]

Here's a more recent paper that mentions some things that might be of interest to you.

 

[Buzz Bloom]

Almost all neurons are terminally differentiated and not able to under go cell division. The common thought is that they are too structurally specialized to divide without losing a lot of their cellular specializations.

Hi Bill:

I remember reading some years ago a book which included what I describe below. Unfortunately I do not remember the author or title, but I do remember the author is a woman.

What had been the spindle structure in the pre-neuron cell (which holds the pairs of paired chromosomes apart during prophase of mitosis) becomes dendrites in the neuron, or an essential part of the dendrites. That is why the neurons cannot reproduce.

ADDED
I did a bit of searching, and I now think I remember the author mentioned above: she is Lynn Margulis. I am still not sure which of her books is the one in which I read about spindles becoming dendrites.

Regards,
Buzz

 

[BillTre]

That almost all neurons don't divide is an observation. There may be a few kinds of neurons able to do this, but not may.

Dendrites and axons both contain a lot of microtubules which are also a major component of mitotic spindles. Its not entirely clear that this is the (or a) reason neurons don't divide, but it does not seem unreasonable.

 

[Buzz Bloom]

That almost all neurons don't divide is an observation. There may be a few kinds of neurons able to do this, but not may.

Dendrites and axons both contain a lot of microtubules which are also a major component of mitotic spindles. Its not entirely clear that this is the (or a) reason neurons don't divide, but it does not seem unreasonable.

Hi Bill:

I have no disagreement with the above quote, but I do have some confusion regarding what seems to be ambiguity.

One interpretation is that there is uncertainty (how much is not specified) about whether or not some neurons divide and reproduce. Similarly there is similar uncertainty regarding whether or not the neuron dendrites have replaced the spindles, and that is the reason neurons don't divide and reproduce.

The ambiguity is "how much"? The quote as it appears now can be interpreted (for example) to mean any of the following:
1. The likelihood some neurons can divide and reproduce is less than 0.01%.
2. The likelihood some neurons can divide and reproduce is greater than 99.99%.
3. The likelihood some neurons can divide and reproduce is greater than 0.01% and less than 99.99%.
4. The reason neurons cannot divide and reproduce is that the spindles have become dendrites is likely to be true with a likelihood less than 0.01%.
5. The reason neurons cannot divide and reproduce is that the spindles have become dendrites is likely to be true with a likelihood greater than 99.99%.
6. The reason neurons cannot divide and reproduce is that the spindles have become dendrites is likely to be true with a likelihood between 0.01% and 99.99%.

I am hopeful you might add some clarity and reduce the degree of ambiguity somewhat.

Regards,
Buzz

 

[BillTre]

1-3: Most kinds of neurons will never divide.
Some kinds of neurons (either different cell types or at different stages of development have been shown to divide (however, some may dispute the way the experiments were done).

4-6: I don't think its known why most don't divide but a common idea has to do with cell cytoskeletion/structure. this may have to do with microtubules. I would not say the spindles have become dendrites, but maybe their tubulin (microtubule protein) has been used to make dendrites. (Tubulin is also used in axons (kind of the opposite of dendrites)).
Forming the spindle might require dissolution of other microtubule structures, cell wide. This may be very disruptive to cell functioning in ways I don't know. That is where I would put most of my bets.
Not going to try to put numbers to things. These are more like handwaving arguments.