Written by Logan Morrison Edited by Dr. Hayley McLoughlin
Research group uncovers the key molecular interaction that causes spinocerebellar ataxia type 1 (SCA1).
When we talk and think about human disease, it is natural to focus on causes. For some disorders, the source of the problem is clear: there’s no question why a patient with a spinal cord injury has paralysis, for instance. Other diseases, like schizophrenia, are incredibly difficult to attribute to specific environmental influences or genetic mutations (probably because they are the result of a variety of subtle factors that add up to cause the disorder).
Our current understanding of spinocerebellar ataxia type 1 (SCA1) falls somewhere in between these extremes. For years, we have known that SCA1 is caused by a polyglutamine expansion in the ataxin-1 gene. In short, this means that SCA1 patients have experienced a rare copying error in their genetic code in the region that is responsible for guiding the production of the Ataxin-1 protein (ATXN1). However, there are still quite a few questions surrounding what ATXN1 does under normal circumstances. This has meant that, so far, scientists have not been able to show why a polyglutamine expansion in the ataxin-1 gene causes the cells of the cerebellum, spine, and brainstem to lose their normal function in cases of SCA1.
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.
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.