Snapshot: What is Neurogenesis?

Neurons are the cells that serve as building blocks of the nervous system. The brain contains an enormous variety of neurons, and they all need to get a start somewhere. The process by which neurons are formed is called neurogenesis.

An artist’s drawing of neurons in the brain. Photo used under license by Andrii Vodolazhskyi/Shutterstock.com.

When does neurogenesis happen?

Nearly all neurogenesis occurs before the age of 2 when the brain is in the early stages of being formed and refined. While most cells in the body are replaced as they wear out or get injured, neurons in the brain do not. By young adulthood, the brain has largely stopped making new neurons. Other than serving as an excellent reason to wear a helmet and otherwise protect your head from injury, this lack of new neuron formation doesn’t have a noticeable effect on how we go about our daily lives. After all, neurons are an incredibly adaptable cell type that readily change in response to a person’s environment and experiences.

In the past few decades, we have learned that there is an exception to the “all neurons are born early in life” rule. Some research has shown that new neurons can, in fact, be formed during adulthood in specific brain areas. For example, the hippocampus, a brain structure important for its role in forming and maintaining memories, continues to create neurons over the course of one’s life.

The purpose of these newly generated neurons is still debated. However, numerous studies have shown that neuron formation in the hippocampus is reduced in instances of psychiatric and neurodegenerative disorders. This includes certain types of ataxia like SCA1. This is thought to contribute to changes in cognitive function and mood, though the exact mechanisms are still being determined.

Why is neurogenesis interesting for the spinocerebellar ataxias (SCAs), aren’t these neurodegenerative disorders?

Since the discovery of neurodegenerative disorders, most research has focused on symptoms and how to delay symptom onset. This view sees neurodegenerative disorders, like the SCAs, as outcomes of mid to late-life when the toxic effects of mutant proteins become suddenly rampant. However, these disorders are caused by proteins that are present from the very earliest stages of brain formation.

In 2018, researchers studying SCA1 found that neurogenesis is increased in the cerebellum of young mice. This changed how the cerebellum communicates with the rest of the brain. This suggests that cerebellar function can be affected by more than neuronal loss. It could be of wider interest in the SCAs given the cerebellar dysfunction that is common between them. No research on cerebellar neurogenesis has been performed in other SCAs by this point. However, there are some indications that neurogenesis may also be altered in SCA2.

Additionally, Huntington’s Disease, a polyglutamine repeat disorder in the same disease family as several SCAs, has been shown to have increased neurogenesis in the cortex in both young mice and prenatal babies. The combination of these recent studies has made early neuron formation an area of key interest in the study of neurodegenerative disorders.

Current theories in the field contend that while the brain can compensate for changes in neuron numbers in early life, altered neurogenesis could be creating unique brain circuitry in individuals with known disorder-causing protein mutations. These changes could make them more vulnerable to neuronal dysfunction and neurodegeneration later in life.

Evidence for changed neurogenesis in SCAs, both early and late in life, adds a new layer of consideration to what we broadly think of as a mid- to late-life neurodegenerative disease. Additional research in coming years will hopefully provide more insight into how these additional facets of neural health may inform the development of new therapies.

If you would like to learn more about neurogenesis, take a look at these resources by the Queensland Brain Insitute and News-Medical.

Snapshot written by Carrie Sheeler and edited by Dr. Chloe Soutar.

Additional References

Cvetanovic M, Hu YS, Opal P. Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1. Cerebellum. 2017 Apr;16(2):340-347. doi: 10.1007/s12311-016-0794-9. PMID: 27306906; PMCID: PMC5510931.

Shukla JP, Deshpande G, Shashidhara LS. Ataxin 2-binding protein 1 is a context-specific positive regulator of Notch signaling during neurogenesis in Drosophila melanogaster. Development. 2017 Mar 1;144(5):905-915. doi: 10.1242/dev.140657. Epub 2017 Feb 7. PMID: 28174239; PMCID: PMC5374347.

Xia G, Santostefano K, Hamazaki T, Liu J, Subramony SH, Terada N, Ashizawa T. Generation of human-induced pluripotent stem cells to model spinocerebellar ataxia type 2 in vitro. J Mol Neurosci. 2013 Oct;51(2):237-48. doi: 10.1007/s12031-012-9930-2. Epub 2012 Dec 9. PMID: 23224816; PMCID: PMC3608734.

Barnat M, Capizzi M, Aparicio E, Boluda S, Wennagel D, Kacher R, Kassem R, Lenoir S, Agasse F, Braz BY, Liu JP, Ighil J, Tessier A, Zeitlin SO, Duyckaerts C, Dommergues M, Durr A, Humbert S. Huntington’s disease alters human neurodevelopment. Science. 2020 Aug 14;369(6505):787-793. doi: 10.1126/science.aax3338. Epub 2020 Jul 16. PMID: 32675289; PMCID: PMC7859879.

Elongating expansions in HD and SCA1

Written by Dr. Marija Cvetanovic  Edited by Dr. Larissa Nitschke

Expanded CAG repeats are the cause of Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). Longer inherited CAG expansions correlate with the earlier disease onset and worse symptoms. We know from past research that these expansions are unstable and become longer from one generation to the next.

This study by Mouro Pinto and colleagues shows that repeat expansions also keep getting longer throughout life in patients affected with HD and SCA1 in many cells, including brain, muscle, and liver cells.

Expansion of CAG repeats in different human genes cause several neurodegenerative diseases. This includes Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). These long CAG repeats in disease genes tend to be unstable in the sperm and egg cells. This instability in sperm and egg cells can result in either longer repeat tracts (expansions) or shorter ones (contractions) in the children of affected patients. Unfortunately, CAG repeats more often expand than shrink. This results in a worse disease in the affected children, with earlier onset and more severe symptoms than their parents.

However, repeat instability and expansion of repeats are not confined to the sperm and egg cells. It can occur in many cells in a patient’s body. This ongoing expansion that occurs in other body cells is called somatic expansion.

Abstract background of DNA sequence
Long CAG repeats in disease genes can be unstable and expand. Photo used under license by Enzozo/Shutterstock.com.

As affected patients age, the ongoing somatic expansion, especially in the brain, may accelerate the onset of neuronal dysfunction and loss of neurons and. This may worsen the disease progression. This has been previously shown in mouse models and patients with HD. However, those studies examined expansion in only a few brain regions and tissues outside the brain (called peripheral tissues).

In this study lead by Dr. Vanessa C. Wheeler, the authors systematically examined repeat instability in 26 different regions of the brain, post-mortem cerebrospinal fluid (CSF) and nine peripheral tissues, including testis and ovaries from seven patients with HD and one patient with SCA1.

Continue reading “Elongating expansions in HD and SCA1”

Spotlight: The Neuro-D lab Leiden

Principal Investigator: Dr. Willeke van Roon-Mom

Location: Leiden University Medical Centre, Leiden, The Netherlands

Year Founded: 1995

What disease areas do you research?

What models and techniques do you use?

A group photo of members of the Neuro-D lab Leiden standing outside on a patio.
This is a group picture taken during our brainstorm day last June. From left to right: Boyd Kenkhuis, Elena Daoutsali, Tom Metz, Ronald Buijsen, Willeke van Roon-Mom (PI), David Parfitt, Hannah Bakels, Barry Pepers, Linda van der Graaf and Elsa Kuijper. Image courtesy of Ronald Buijsen.

Research Focus

What is your research about?

The Neuro-D research group studies how diseases develop and progress at the molecular level in several neurodegenerative diseases. They focus on diseases that have protein aggregation, where the disease proteins clump up into bundles in the brain and don’t work correctly.

We focus strongly on translational research, meaning we try to bridge the gap between research happening in the laboratory to what is happening in medical clinics. To do this we use more “traditional” research models like animal and cell models. But we also use donated patient tissues and induced pluripotent stem cell (iPSC) models, which is closer to what is seen in medical clinics.

Our aim is to unravel what is going wrong in these diseases, then discover and test potential novel drug targets and therapies.

One thing we are doing to work towards this goal is identifying biomarkers to measure how diseases progress over time. To do this, we use sequencing technology and other techniques to look at new and past data from patients.

Why do you do this research?

So far there are no therapies to stop the progression of ataxia. If we can understand what is happening in diseases in individual cells, we can develop therapies that can halt or maybe even reverse disease progression.

Identifying biomarkers is also important, because it will help us figure out the best time to treat patients when we eventually have a therapy to test.

Stylized logo for the Dutch Center for RNA Therapeutics
The Neuro-D lab Leiden is part of the Dutch Center for RNA Therapeutics, which focuses on RNA therapies like antisense oligonucleotides. Logo designed by Justus Kuijer (VormMorgen), as 29 year old patient with Duchenne muscular dystrophy.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for a SCA1 natural history study and biomarker study. More information can be found here. Please note that information about this study is only available in Dutch.

Fun Fact

All our fridges and freezers have funny names like walrus, seal, snow grouse and snowflake.

For More Information, check out the Neuro-D lab Leiden website!


Written by Dr. Ronald Buijsen, Edited by Celeste Suart

Spotlight: The Truant Lab

Truant lab logo of a brain. "Bright minds fixing sick brains"

Principal Investigator: Dr. Ray Truant

Location: McMaster University, Hamilton, Ontario, Canada

Year Founded: 1999

What disease areas do you research?

  • SCA1
  • SCA7
  • Huntington’s Disease
  • Parkinson’s Disease

What models and techniques do you use?

  • Human cell biology
  • High content screening
  • Biophotonics
  • Microscopy

Research Focus

What is your research about?

We are looking into the role of oxidative DNA damage as a trigger to diseases like ataxia and neurodegeneration. We examine the roles of the disease proteins (ataxin-1, ataxin-7, etc,) and genes which modify or change disease that are involved with DNA damage repair.

Why do you do this research?

We are looking at what triggers the very first steps of disease. If we can understand this, we can design a treatment to stop it from happening in the first place.

Research team of 10 holding a sign which reads "We are Ataxia Aware"
Group picture of the Truant Laboratory celebrating International Ataxia Awareness Day 2019.

Fun Lab Fact

All our fridges in the laboratory are named after Game of Thrones characters! (We have several proud nerds in the lab)

For More Information, check out the Truant Lab Website!

We have an open lab notebook blog where our post-doctoral fellow Dr. Tam Maiuri post updates on her experiments in real-time! We plan to launch an ataxia open notebook in Winter 2021.


Written by Ray Truant, Edited by Celeste Suart

New molecule can reverse the Huntington’s disease mutation in lab models

Written by Dr. Michael Flower Edited by Dr. Rachel Harding

Editor’s Note: This article was initially published by HDBuzz on March 13, 2020. They have graciously allowed us to build on their work and add a section on how this research may be relevant to ataxia. This additional writing was done by Celeste Suart and edited by David Bushart.

A collaborative team of scientists from Canada and Japan have identified a small molecule which can change the CAG-repeat length in different lab models of Huntington’s disease.

CAG repeats are unstable

Huntington’s disease is caused by a stretch of C, A and G chemical letters in the Huntingtin gene, which are repeated over and over again until the number of repeats passes a critical limit; at least 36 CAG-repeats are needed to result in HD.

In fact, these repeats can be unstable, and carry on getting bigger throughout HD patients’ lives, but the rate of change of the repeat varies in different tissues of the body.

In the blood, the CAG repeat is quite stable, so an HD genetic blood test result remains reliable. But the CAG repeat can expand particularly fast in some deep structures of the brain that are involved in movement, where they can grow to over 1000 CAG repeats. Scientists think that there could be a correlation between repeat expansion and brain cell degeneration, which might explain why certain brain structures are more vulnerable in HD.

a print out of genetic information show as a list of A,T, C, and G letters
The CAG repeat of the huntingtin gene sequence can be changed to include more and more repeats, in a process called repeat expansion. This can also happens in some ataxia related genes. Image credit: “Gattaca?” by IRGlover is licensed under CC BY-NC 2.0

But why?

This raises the question, what is it that’s causing the CAG repeat to get bigger? It seems to be something to do with DNA repair.

We’re all exposed continually to an onslaught of DNA damage every day, from sunlight and passive smoking, to ageing and what we eat. Over millions of years, we’ve evolved a complex web of DNA repair systems to rapidly repair damage done to our genomes before it can kill our cells or cause cancer. Like all cellular machines, that DNA repair machinery is made by following instructions in certain genes. In effect, our DNA contains the instructions for repairing itself, which is quite trippy but also fairly cool.

What is it that’s causing the CAG repeat to get bigger? 

We’ve known for several years that certain mouse models of HD have less efficient systems to repair their DNA, and those mice have more stable CAG repeats. What’s more, deleting certain DNA repair genes altogether can prevent repeat expansion entirely.

But hang on, isn’t our DNA repair system meant to protect against mutations like these?? Well normally, yes. However, it appears a specific DNA repair system, called mismatch repair, sees the CAG repeat in the huntingtin gene as an error, and tries to repair it, but does a shoddy job and introduces extra repeats.

Why does this matter?

There’s been an explosion of interest in this field recently, largely because huge genetic studies in HD patients have found that several DNA repair genes can affect the age HD symptoms start and the speed at which they progress. One hypothesis to explain these findings is that slowing down repeat expansion slows down the disease. What if we could make a drug that stops, or even reverses repeat expansion? Maybe we could slow down or even prevent HD.

Continue reading “New molecule can reverse the Huntington’s disease mutation in lab models”