Nav: Home

New iPS-cell model system helps develop treatments for spinocerebellar ataxia

November 01, 2016

Researchers at the RIKEN Center for Developmental Biology have succeeded in creating a new model system that can be used to develop drug therapies for genetic disorders like spinocerebellar ataxia type 6 (SCA6). Published in Cell Reports, the study shows how stem cells from patients with SCA6 can be transformed into mature Purkinje cells -- the same type of neuron that starts dying when people develop SCA6 later in life. With this setup, the team discovered that mature Purkinje cells with the SCA6 mutation became vulnerable when deprived of thyroid hormone.

SCA6 is a movement disorder characterized by death of Purkinje cells in the cerebellum, a brain region that controls our ability to produce smooth movements. No effective treatment or cure exists for this neurodegenerative disorder, and animal models have proved inconclusive. As an alternative, the team led by Keiko Muguruma focused their efforts on making a disease model based on human Purkinje cells grown in culture.

As Muguruma explains, "we succeeded in generating Purkinje cells with full sets of SCA6 patient genes. Unlike animal models, these patient-derived Purkinje cells will be extremely useful for investigating disease mechanisms and for developing effective drug therapies."

The disease manifests in middle age and results from mutations that increase the number of times a particular section of the CACNA1A gene are repeated. The researchers first induced skin or blood cells from patients and control participants to become pluripotent stem cells. Then they used techniques recently developed in their lab to create self-organizing cerebellar tissue and Purkinje cells.

When tested, the team found that while both types of mature Purkinje cells seemed outwardly similar, they differed in how much the CACNA1A gene was expressed. The patient-derived cells contained more of the protein encoded by the CACNA1A gene than the normal cells. When immature cells were tested, protein expression levels were similar, regardless of their origins.

The part of the CACNA1A protein that contains the excessively repeated section is called α1ACT. When researchers compared expression of this fragment between normal and patient-derived cells, they found that it was expressed much less in the SCA6 Purkinje cells. Because α1ACT normally binds to DNA in the nucleus and triggers the expression of other proteins that are important for normal Purkinje-cell development, these proteins were also expressed much less in the cells that contained the mutation. Again, when the team looked at immature Purkinje cells, α1ACT expression was similar for all groups.

"This new system is particularly useful for drug discovery," notes Muguruma. "Using it, we were able to demonstrate that patient-derived Purkinje cells show a vulnerability to nutrient depletion and that this vulnerability can be suppressed by several compounds."

Knowing that thyroid hormone is important for proper maturation and maintenance of Purkinje cells, the researchers deprived mature neurons of the hormone and found that many of the patient-derived cells died, while those that survived showed physical abnormalities. Purkinje cells without the mutation were unaffected. Further testing showed that even when deprived of thyroid hormone, negative changes in SCA6 Purkinje cells could be prevented using thyroid releasing hormone. Similar results occurred with Riluzole, a drug often used to treat another neuromuscular disorder called ALS -- also known as Lou Gehrig's disease.

Decreased thyroid gland activity, a condition known as hypothyroidism, also occurs with age, and might be linked to SCA6 onset. Muguruma cautions, "there are some reports that hypothyroidism is related to cerebellar ataxia and cerebellar atrophy, but we do not yet know whether the SCA6 disease phenotypes are causally linked to decreased thyroid hormone."

Now that they have proved the usefulness of this model system, Muguruma and her colleagues can continue to investigate how thyroid releasing hormone was able to protect the cells, and ultimately find a cure for this type of spinocerebellar ataxia.
-end-
Reference:

Ishida Y, Kawakami H, Kitajima H, Nishiyama A, Sasai Y, Inoue H, Muguruma K (2016). Vulnerability of Purkinje cells generated from spinocerebellar ataxia type 6 patient-derived iPS cells. Cell Reports. doi: 10.1016/j.celrep.2016.10.026.

RIKEN

Related Stem Cells Articles:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.
More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.
Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.
First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.
Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.
The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.
Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.
New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.
NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.
Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.
More Stem Cells News and Stem Cells Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Warped Reality
False information on the internet makes it harder and harder to know what's true, and the consequences have been devastating. This hour, TED speakers explore ideas around technology and deception. Guests include law professor Danielle Citron, journalist Andrew Marantz, and computer scientist Joy Buolamwini.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.