Early Cerebellum Development Abnormality in Adult-Onset Spinocerebellar Ataxia Type 1

Written by Dr. Vitaliy V Bondar  Edited by Dr. Chandrakanth Edamakanti

Researchers for the first time identified that spinocerebellar ataxia type 1 (SCA1) may have roots in early cerebellar circuit malfunction.

Cartoon of a neuron
Artist representation of a neuron. Image courtesy of Pixabay

Since the discovery of the cause of SCA1, researchers have wondered: why does it take three to four decades of life for symptoms to reveal themselves? This late stage disease progression is surprising, given that early molecular changes are observed in many SCA1 animal models. Furthermore, this is true for many other neurodegenerative diseases (i.e., that molecular changes precede symptoms). Studying and understanding this delay in symptom onset may reveal potential treatment options to mitigate and slow down the progression of the disease.

The cerebellum is one of the most important brain regions for SCA1 research because it is responsible for the fine movement control that SCA1 patients have difficulty with. Moreover, the cerebellum is the brain region that degenerates the earliest in SCA1. Given that SCA1 symptoms strike late in adulthood, many scientists thought that there would not be any cellular changes during the cerebellum’s development (that is, early in SCA1 patients’ lives). However, Chandrakanth Edamakanti, a postdoctoral scientist in Puneet Opal’s laboratory at Northwestern University, has recently demonstrated that the stem cells in the cerebellum behave differently in SCA1. These stem cells, which exist in the cerebellum for the first three weeks after birth, help to complete cerebellar development by adding new neurons and supporting cells (known as glia). Dr. Edamakanti and colleagues have shown that, in SCA1, this process is disturbed, which likely contributes to Purkinje cell toxicity at later ages. This represents the first cellular and anatomical difference that has been seen in neurons prior to degeneration in SCA1. Other neurodegenerative diseases, including Alzheimer’s, Huntington’s and Parkinson’s, may also stem from such developmental defects that set the stage for later disease vulnerability.

SCA1, like most neurodegenerative diseases, shows up in late adulthood and is characterized by cell loss in a specific brain region. What separates SCA1 from other diseases is that the cells that are lost are in the cerebellum, a part of the brain that controls movement. Specifically, the main pathological hallmark of the disease is the loss of Purkinje cells in the cerebellum and, later, overall cerebellar atrophy. Given that the molecular changes seen in SCA1 happen very early in life, it is surprising that cell loss happens much later. For example, in an SCA1 mouse model, gene expression changes occur as early as the first week of birth, but neuronal loss is only visible many weeks later. In this study, researchers identified the reason for this gap in time between molecular and cellular changes: the appropriate balance in the identity of the cells in the cerebellum is affected in SCA1.

The cerebellum is composed of many different cells that are generally divided into glia and neurons. Glia are composed of a few different cell types, most of which are primarily responsible for supporting and protecting neurons. Neurons are the primary cells that signal to transmit information such as touch, sound, or light throughout the brain. Early on in SCA1, during the development of the cerebellum, glia production is reduced while the number of neurons is increased. The developmental cells that can give rise to both cell types in the cerebellum are referred to by scientists as stem cells. Interestingly, in SCA1, it appears that stem cells are generating more basket cells (a type of neuron) and less astrocytes (a type of glia) during cerebellar development. Neurons are usually divided into excitatory and inhibitory sub-types, which stimulate or inhibit other neurons, respectively. Since basket cells are inhibitory neurons, their elevated number in the SCA1 cerebellum causes inhibition of downstream cells they are transmitting information to, called Purkinje cells. This discovery reveals that, during cerebellar development, the SCA1 cerebellum has more stem cells, which subsequently causes an increase in the number of inhibitory basket cells and a decrease in the number of supporting astrocytes. This enhanced basket cell population forms an exaggerated connection with Purkinje cells, inhibiting their activity more than normal. This is one of the first studies that reports the toxicity of Purkinje cells in SCA1 may come from the surrounding cell population. It is unclear what triggers this increase in the stem cell population, and why basket cell/astrocyte populations are skewed, but the finding provides the first insight into the delay of symptoms in SCA1. As it turns out, cellular differences do actually occur early in the SCA1 cerebellum, we just did not look at the right place and with the appropriate tools.

The authors of this study used a genetically engineered mouse model of SCA1 that displays symptoms similar to those seen in patients. To visualize different cell types, researchers used molecular markers that are each specifically attracted to one type of cell. Using these markers, the scientist counted the different cell types at various ages to identify early developmental changes in the cerebellum of their SCA1 mouse model. To confirm the results they observed in mice, scientist looked at postmortem brains of unaffected and SCA1 individuals to demonstrate that their findings in mice hold true in humans as well.

Since each cell type has a unique molecular signature, this discovery could very well explain why molecular differences are observed early in life. Moreover, improper balance of cell types in the cerebella of SCA1 patients might potentially explain late-onset neurodegeneration: while the lack of glia in the cerebellum may not cause the death of neurons right away, death might be triggered later in life after cells have accumulated years of mild damage. Lack of sufficient support from fewer astrocytes and increased inhibition of Purkinje cells by an elevated number of basket cells may provide the stress that eventually causes neurodegeneration in SCA1. Future studies on molecular mechanisms of skewed cell identify in the SCA1 cerebellum may provide therapeutic targets to slow down the progression of symptoms.

Key Terms

Stem Cells: Early developmental cells that duplicate themselves many times and give rise to multiple different cell types.

Glia: Non-neuronal cells that are primarily responsible for supporting neurons. They are divided into several different types.

Purkinje Cells: A type of neuron in the cerebellum, which are some of the largest neurons in the brain. They help regulate fine movement. Purkinje cell loss/pathology is a common feature in cerebellar ataxia.

Basket cells: Inhibitory neurons that transmit information to Purkinje cells.

Astrocytes: Types of glia that support neurons through a variety of means, like providing nutrients.

Conflict of Interest Statement

The author has no conflicts of interests to declare. The editor was the primary author on the scientific article being reviewed. 

Citation of Article Reviewed

Edamakanti, C.R., Do, J., Didonna, A., Martina, M., Opal, P. Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1. The journal of Clinical Investigation. 2018. 128(6): 2252-2265 https://www.ncbi.nlm.nih.gov/pubmed/29533923