Adult Onset Neurodegeneration Has Roots in Early Development

Summary: Gene expressions in the brain that occur early in development may explain why some cerebellar stem cell populations behave differently in people with SCA1, researchers report.

Source: Northwestern University.

The disease mechanism for adult-onset progressive degenerative diseases begins much earlier than previously thought, according to a Northwestern Medicine study published in the Journal of Clinical Investigation.

Using a mouse model of spinocerebellar ataxia type 1 (SCA1) genetically engineered to precisely mirror the human disease, a team of investigators showed that there is an altered neural circuitry in the cerebellum that sets the stage for later disease vulnerability.

These findings are important since they raise the possibility that other adult-onset neurodegenerative diseases have their roots in early developmental defects, with implications for pathogenesis and treatment, said Puneet Opal, MD, PhD, professor in Ken & Ruth Davee Department of Neurology at Northwestern University Feinberg School of Medicine, and senior author on the study.

“This is the first discovery of alterations in an adult-onset spinocerebellar disorder that stem from such early developmental processes,” said Opal, also a professor of Cell and Molecular Biology. “This may well be generalizable to a whole host of other diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.”

SCA1 is caused by a genetic defect in a protein involved in regulating gene expression called ATXN1. While ATXN1 is expressed throughout the brain, when mutated it predominantly affects the cerebellum, leading to a loss of coordination and an abnormal gait in patients.

Previous studies have largely focused on neurons in the disease, but Opal and his colleagues theorized the cerebellar stem cell population might also behave differently since some of the gene expression changes in the brain in the disease occur relatively early.

Using a genetically engineered mouse model of the disease, the scientists found that mutant ATXN1 had surprising effects on postnatal cerebellar stem cells.

“We were amazed to find that they multiplied excessively and tended to differentiate into inhibitory neurons called basket cells,” said Opal. “We knew that cerebellar stem cells generate inhibitory neurons, but in this case the number of inhibitory neurons was so much more than normal that they generated an enhanced inhibitory effect on Purkinje neurons, the chief output neurons of the cerebellum. This results in a very different cerebellar network.”

These changes began in the early postnatal weeks of life and may explain why the cerebellar neuronal network is particularly vulnerable to degeneration in patients with SCA1, according to Opal.

Neurofascin staining reveals processes of basket cells surrounding Purkinje neurons in the cerebellum. image is credited to the researchers.

In addition, as more stem cells became inhibitory neurons, fewer stem cells became brain cells called astrocytes, possibly further disrupting normal cerebellar function.

“This network dysfunction could be a constant stress, and that constant stress makes the neural network deteriorate over time,” Opal said.

While it’s still unclear exactly how the mutant protein is causing these changes, according to the study, the findings underscore the need to study a relatively underappreciated phenomenon: that pathogenic processes in neurodegenerative diseases begin very early in life– well before signs or symptoms are noticed.

“Other diseases may have similar developmental defects, but we haven’t looked for them,” Opal said. “We found them in SCA1, but it could be true for the other diseases as well.”

About this neuroscience research article

Chandrakanth Reddy Edamakanti, PhD, postdoctoral fellow in Opal’s laboratory, was lead author on the study. Other Feinberg authors on this study include Marco Martina, MD, PhD, associate professor of Physiology and Jeehaeh Do, fourth-year student in the Northwestern University Interdepartmental Neuroscience (NUIN) graduate program.

Funding: This study was supported by National Institutes of Health grants 1R01 NS062051, 1R01 NS082351 and 1R21NS090346.

Source: Marla Paul – Northwestern University
Publisher: Organized by
Image Source: image is credited to the researchers.
Original Research: Abstract for “Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1” by Chandrakanth Reddy Edamakanti, Jeehaeh Do, Alessandro Didonna, Marco Martina, and Puneet Opal in Journal of Clinical Investigation. Published March 13 2018.

Cite This Article

[cbtabs][cbtab title=”MLA”]Northwestern University “Adult Onset Neurodegeneration Has Roots in Early Development.” NeuroscienceNews. NeuroscienceNews, 30 March 2018.
<>.[/cbtab][cbtab title=”APA”]Northwestern University (2018, March 30). Adult Onset Neurodegeneration Has Roots in Early Development. NeuroscienceNews. Retrieved March 30, 2018 from[/cbtab][cbtab title=”Chicago”]Northwestern University “Adult Onset Neurodegeneration Has Roots in Early Development.” (accessed March 30, 2018).[/cbtab][/cbtabs]


Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1, which is involved in transcriptional regulation. Although symptoms appear relatively late in life, primarily from cerebellar dysfunction, pathogenesis begins early, with brain-wide transcriptional changes detectable as early as a week after birth in SCA1 knock-in mice. Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant ATXN1. We found that expanded ATXN1 stimulates the proliferation of postnatal cerebellar stem cells in SCA1 mice. These hyper-proliferating stem cells tended to differentiate into GABAergic inhibitory interneurons rather than astrocytes; this significantly increased the GABAergic inhibitory interneuron synaptic connections, disrupting cerebellar Purkinje cell function in a non-cell autonomous manner. We confirmed the increased basket cell-Purkinje cell connectivity in human SCA1 patients. Mutant ATXN1 thus alters the neural circuitry of the developing cerebellum, setting the stage for the later vulnerability of Purkinje cells to SCA1. We propose that other late-onset degenerative diseases may also be rooted in subtle developmental derailments.

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