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.

Eliminación de la proteína ataxina-2 agregada como vía terapéutica para SCA2

Escrito por el Dr. Vitaliy Bondar Editado por el Dr. Hayley McLoughlin. Publicado inicialmente en el 5 de febrero de 2021. Traducción al español fueron hechas por FEDAES y Carlos Barba.

Una nueva investigación sugiere que la proteína ataxina-2 mutante abruma a las células en SCA2, lo que lleva a una disminución de la autofagia y la eliminación de las proteínas dañadas.

Se pueden hacer muchas comparaciones entre células y seres humanos. Al igual que los humanos, las células pueden acumular basura y desechos en ciertos momentos y este desorden con el tiempo se vuelve problemático e incluso tóxico. Esto es precisamente lo que Jonathan Henry Wardman y sus colegas de la Universidad de Copenhague decidieron investigar a nivel celular. Preguntaron si la falta de una eliminación adecuada de las proteínas defectuosas de la enfermedad afecta la supervivencia y el bienestar celular.

Los investigadores optaron por estudiar células derivadas de un paciente que tiene ataxia espinocerebelosa tipo 2 (SCA2). La causa de SCA2 es la expansión de la repetición CAG en el gen ATAXIN-2 , que codifica la cadena de aminoácidos de poliglutamina en una proteína de unión al ARN , ataxina-2. Se encuentra que la proteína ATXN2 expandida poliQ defectuosa se agrega dentro de la célula y las horas extraordinarias pueden afectar su supervivencia. La acumulación de productos proteicos agregados derivados de genes mutados es un sello distintivo de muchos tipos de ataxias espinocerebelosas, así como de otras formas de trastornos neurodegenerativos como la enfermedad de Parkinson.

No está claro cómo la agregación de proteínas afecta la supervivencia celular. Sin embargo, se han correlacionado múltiples defectos celulares con la agregación de ataxina-2. Por ejemplo, se ha informado que las mitocondrias que generan energía para una célula funcionan de manera anormal en modelos celulares SCA2. Además, un mecanismo de depuración celular, llamado autofagia , que es responsable de limpiar los compartimentos celulares defectuosos y ciertas proteínas rotas, se muestra menos eficaz en varios modelos de SCA2. Estos mecanismos los autores decidieron investigar en su artículo de investigación recientemente publicado.

scientist using microscope
Una nueva investigación que utiliza células SCA2 arroja luz sobre las causas de los síntomas de la enfermedad. Foto de Chokniti Khongchum en Pexels.com

Los científicos identificaron por primera vez la evidencia de disfunción celular SCA2 mediante la detección de una elevación significativa de los niveles de caspasa-9 y caspasa-8. Son proteínas que indican estrés celular y muerte. Los autores plantearon la hipótesis de que dicha disfunción celular puede deberse a la acumulación de ataxina-2 defectuosa. Para probar esta hipótesis, decidieron bloquear sistemáticamente dos vías celulares que procesan proteínas defectuosas: proteostasis y autofagia.

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Results of the RISCA study: gaining a better understanding of how ataxia symptoms first appear in at-risk patients

Written By Dr. David Bushart Edited by Celeste Suart

The RISCA study will help researchers design smarter, more efficient clinical trials by teaching us about the very early stages of SCA

Ataxia research has grown significantly in recent years. Although much work still remains, we are gaining a better understanding of how ataxia affects patients. Several exciting, new therapies are currently being studied. These advances would not be possible without the involvement of ataxia patients in clinical research studies. Some clinical studies are drug trials, where patients are enrolled to help researchers determine whether new therapies are effective at treating ataxia. However, other equally important types of clinical studies also exist. Ataxia patients play a critical role in the success of these studies.

What would an ideal treatment for ataxia look like? Ideally, we would be able to treat patients when their symptoms are very mild, or perhaps even before their symptoms appear at all. However, there are several obstacles to developing and testing this kind of hypothetical treatment:

First, it can be hard to know which patients to treat if symptoms are not yet present! There are many people who descend from patients affected by SCA of some kind. They have a 50% chance of being affected. While some of these people have been genetically tested, many have not. This makes it difficult to predict whether they will eventually develop SCA at all.

Second, along those lines, it could be very difficult to predict whether a drug is working to prevent symptoms from appearing if we don’t know precisely when symptoms should appear. It is much easier to tell if a drug is working when it is given to a patient with obvious symptoms – if their symptoms improve, the drug works.

Third, it can be difficult for researchers to enroll enough patients into clinical trials to get a meaningful result. This is complicated by the fact that we don’t know the answers to the first two questions above. Until recently, it remained unclear how a trial to test such a hypothetical treatment would need to be designed.

Thankfully, recent work has helped us better understand the answers to these questions. Results from the RISCA study were recently released. RISCA, which is a prospective, longitudinal, observational cohort study, was designed to study individuals who are at-risk for developing SCA, and how SCA symptoms might first appear.

Doctor and patient discussing something while sitting at the table
The RISCA study was designed to give doctors and patients more information about when ataxia symptoms first start to appear. This information is incredibly important for future ataxia clinical trials. Photo used under license by S_L/Shutterstock.com.
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Clearing aggregated ataxin-2 protein as a therapeutic avenue for SCA2

Written by Dr. Vitaliy Bondar Edited by Dr. Hayley McLoughlin

New research suggests that mutant ataxin-2 protein overwhelms cells in SCA2, leading to decreased autophagy and clearance of damaged proteins.

Many comparisons can be made between cells and human beings. Just like humans, cells can accumulate junk and waste at certain times and this clutter overtime becomes problematic and even toxic. This is precisely what Jonathan Henry Wardman and colleagues from the University of Copenhagen decided to investigate on a cellular level. They asked whether the lack of appropriate clearance of faulty disease proteins effect cellular survival and wellbeing.

The researchers chose to study cells derived from a patient that has Spinocerebellar ataxia type 2 (SCA2). The cause of SCA2 is CAG repeat expansion in the ATAXIN-2 gene, which encodes polyglutamine amino acid chain in an RNA-binding protein, ataxin-2. The faulty polyQ expanded ATXN2 protein is found to aggregate inside the cell and overtime can affect its survival. Accumulation of aggregated protein products derived from mutated genes is a hallmark of many types of spinocerebellar ataxias as well as other forms of neurodegenerative disorders such as Parkinson’s disease.

It is unclear how protein aggregation impacts cellular survival. However, multiple cellular defects have been correlated with ataxin-2 aggregation. For instance, mitochondria which generates energy for a cell, has been reported to abnormally function in SCA2 cellular models. Additionally, a cellular clearance mechanism, called autophagy, which is responsible for clearing faulty cellular compartments and certain broken proteins is shown to be less effective in various SCA2 models. These mechanisms the authors decided to investigate in their recently published research article.

scientist using microscope
New research using SCA2 cells sheds light on what causes disease symptoms to occur. Photo by Chokniti Khongchum on Pexels.com

The scientists first identified evidence of SCA2 cellular dysfunction through detection of significant elevation of caspase-9 and caspase-8 levels. These are protein which indicate cellular stress and death. The authors hypothesized that such cellular dysfunction may arise from accumulation of faulty ataxin-2. In order to test this hypothesis, they decided to systematically block two cellular pathways that process defective proteins: proteostasis and autophagy.

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A new molecule identified that controls cerebellar communication

Written by Dr. Ambika Tewari Edited by Dr. Sriram Jayabal

Targeting phosphatases in the cerebellum can correct miscommunication in multiple models of ataxia.

The cerebellum is essential for motor coordination and consists of the coordinated activity of different types of cells. Purkinje cells are one of the most fascinating cell types in the cerebellum. They have an elaborate network of branches called dendrites, where a neuron receives communication from other neurons. It is one of the most complex branching systems seen across all neurons in the entire brain. Each one of these branches has many points of contact with other branches called axons. Each axon is part of a neuronal structure that allow communication between neurons. These axons are from different cell types and allow information to be transferred to Purkinje cells.

Colourful illustration of a human brain
Targeting phosphatases in the brain could improve communication between neurons, reducing ataxia symptoms.

Due to this branching complexity, Purkinje cells receive many messages or inputs. This represents different pieces of sensory information to ensure that movements are precisely timed. Purkinje cells must integrate and process this information. This produces motor behaviors like walking, writing, playing a musical instrument, and many more. Any alteration to the processing of this information will result in cerebellum dysfunction; in fact, Purkinje cells have gained attention because they undergo progressive deterioration in most ataxias. 

Neurons, including Purkinje cells, communicate with other neurons using electrical signals known as action potentials or spikes. Firing rate, defined as the number of spikes within a defined period of time, is thought to be an important feature of this communication, which is critical for coordinating muscle movements. Therefore, a lower firing rate in Purkinje cells would signal a faulty communication between Purkinje cells and their targets. This has devastating consequences as seen in many ataxias.

For instance, in an earlier study, a group of authors found that the firing rate of Purkinje cells was decreased in mouse models of three different Spinocerebellar ataxias (SCAs): SCA1, SCA2, and SCA5. They further explored whether there was a common reason underlying the decreased firing rate. They found that a protein named Missing in Metastasis (MTSS1), was important for Purkinje cells to effectively communicate with each other. Mice engineered to have no MTSS1 protein had a decreased firing rate and difficulty walking and maintaining their balance.

In every cell in the body, including brain cells, there are numerous proteins that perform different functions. The concerted effort of all are needed for the cell to perform its intended duty. Some of these proteins are maintained in the cell in an inactive form and are activated when they are required in the cell and inhibited when they are not. This highly regulated system aims to maintain precise levels of proteins in each cell, while simultaneously conserving energy. Each cell has many ways of activating/inactivating a protein. A specialized group of proteins known as kinases and phosphatases, adds and removes phosphate groups to and from proteins respectively, thereby altering their active/inactive forms which then changes their interactions with other proteins. MTSS1 is one such protein that inhibits the activity of a group of kinases known as Src family of non-receptor tyrosine kinases (SFKs).

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