Discoveries Could Slow Dysfunction in Spinocerebellar Ataxia Type 1

Two different approaches to treating spinocerebellar ataxia type 1 – aerobic exercise or delivery of vascular endothelial growth factor – appeared to halt or slow the dysfunction of vulnerable cerebellar and brain stem cells in separate studies of a mouse model that closely mirrors the human disease.

The studies also shed light on how the poly-glutamine repeat mutation found in the AXTN1 gene of patients with spinocerebellar ataxia type 1 (SCA1) affects the transcription of particular genes that may contribute to the disease’s hallmark pathology of atrophy and loss of Purkinje neurons from the cerebellar cortex.

Patients with SCA1 most often initially experience problems with gait and balance, followed later by other motor difficulties, cognitive impairment, and sometimes sensory neuropathy, dystonia, and muscle atrophy and fasciculations.

Exercise Increased Life Span

The researchers, led by John D. Fryer, Ph.D., at Baylor College of Medicine, Houston, found that a regimen of relatively light exercise 5 days per week at an early age extended the life of mice with SCA1 by up to 6 weeks but did not improve their motor performance. This exercise led to a sustained increase in the level of epidermal growth factor (EGF) in the brain stem but not in the cerebellum (Science 2011;334:690-3).

The investigators also looked at how exercise affected the function of a transcriptional repressor protein called Capicua (Cic) that interacts with the ATXN1 gene’s protein product (ataxin 1) and lies downstream of EGF signaling.

Levels of Cic in SCA1 mice declined in the brainstem but not in the cerebellum after the exercise training period. Similarly, when brainstem neuronal cultures from SCA1 mice were exposed to EGF, levels of Cic declined. This suggested that a reduction of Cic itself might improve the survival of the SCA1 mice.

Further experiments showed that genetically reducing the level of Cic by 50% in SCA1 mice significantly improved their motor coordination, learning, and memory deficits; curbed the loss of Purkinje cells at 40 weeks of age; and extended their life span.

Genetic reduction of Cic improved motor coordination, according to Dr. Fryer and his coauthors. However, exercise on its own or in the amount undertaken in the first group of SCA1 mice did not improve motor coordination, judging from the observation that it lowered Cic levels only in the brainstem rather than in the cerebellum.

The investigators suggested that the deleterious effects of mutant ataxin 1 may be moderated by lower levels of Cic because the mutant protein appeared to cause a simultaneous increase or decrease in Cic’s transcriptional repression of certain genes. Based on these results, the researchers thought that therapeutics aimed at lowering Cic levels or disrupting the interaction between Cic and mutant ataxin 1 "could potentially ameliorate the disease."

Because the effect of exercise on life span lasted long after the mice stopped exercising, they suggested that "SCA1 individuals might benefit from an exercise program early in disease course." They described the exercise regimen as being "quite gentle," so they could not rule out "the possibility that more intense or longer-duration exercise could cause a sustained EGF increase and Cic decrease in the cerebellum that could lead to motor improvements."

Dr. S. H. Subramony, codirector of the ataxia clinic in the movement disorder center at the University of Florida, Gainesville, said in an interview that the study gives greater weight for the potential use of exercise training in neurodegenerative diseases. Exercise training has not been studied, to his knowledge, in individuals with SCA1. "I think we increasingly recognize that physical activity has numerous biochemical effects, many beneficial, including changes in gene transcription."

There is evolving evidence that suggests exercise in general increases life span, "so whether there is a specific effect of exercise on SCA1 pathogenesis or a general effect is not clear to me because they do not show a SCA1-specific effect in terms of motor performance and pathology in the cerebellum, but the parallel biochemical evidence suggests that it might" said Dr. Subramony, who was not involved with the study.

It remains to be clarified whether exercise needs to start before the onset of symptoms or can be begun after or how intense it needs to be, noted Dr. Subramony, who also is director of the neuromuscular division in the department of neurology at the university.

Another Growth Factor at Work in SCA1

Another study on SCA1 mice supports the notion that mutant ataxin 1 has a toxic gain of function in repressing the transcription of certain genes. Marija Cvetanovic, Ph.D., of Northwestern University, Chicago, found that another growth factor, vascular endothelial growth factor (VEGF), also is transcriptionally repressed by mutant ataxin 1.

Dr. Cvetanovic and her associates found that the expression of the gene for VEGF, an angiogenic and neurotrophic growth factor, was downregulated in the cerebellar Purkinje neurons of SCA1 mice before they showed any behavioral or pathologic signs of the disease. Mutant ataxin 1 directly repressed the expression of VEGF mRNA in the mice. The mutation of a site on the protein known to be crucial for its toxicity stopped its ability to repress the transcription of VEGF; this demonstrated that the repression of VEGF correlates with the in vivo toxicity of the mutant protein (Nat. Med. 2011;17:1445-7).

The researchers observed that VEGF repression induced hypoxia and also limited angiogenesis in the cerebellum of SCA1 mice by significantly decreasing cerebellar microvessel density and total vessel length. Inhibition of VEGF signaling in cerebellar neuronal cultures also decreased neurite length and increased cell death.

However, the genetic overexpression of VEGF beginning during embryonic development in SCA1 mice enhanced their motor performance at 13 weeks and 6 months of age and improved their cerebellar pathology. In other SCA1 mice, continuous intracerebroventricular delivery of VEGF after the onset of disease led to similar improvements.

"Our findings suggest a role for VEGF in SCA1 pathogenesis and indicate that restoring VEGF levels may be a potentially useful treatment in patients with SCA1," the researchers concluded.

When asked to comment on this research, Dr. Subramony called the VEGF study "elegant," but noted that studies of growth factors for other diseases have had generally disappointing results in translating murine data to humans. Another concern for translating the study to humans is in getting the molecule to enough of the affected area in human brains, which is less of a problem with very small mouse brains.

In addition, the literature suggests that mutant ataxin 1 causes dysregulation of many genes, not just VEGF, so "the possibility remains that just replacing VEGF may not rescue the disease in a more comprehensive manner because we know that a number of other genetic alterations take place in these tissues because of the mutation," he said.

"From a clinical perspective, it may be easier to translate the exercise study to humans because it is easier to put patients through an exercise program than to give them a novel molecule" such as VEGF, which to Dr. Subramony’s knowledge has not been studied in a human trial for any disease.

The exercise study was supported by grants from the National Institutes of Health (NIH). Dr. Fryer performed the research for the exercise study at Baylor, but he is now at the Mayo Clinic in Jacksonville, Fla. The VEGF study was supported by grants from the NIH, the U.S. National Organization for Rare Disorders, the U.S. Brain Research Foundation, and the U.S. National Ataxia Foundation. None of the authors of that study had relevant financial disclosures. Dr. Subramony said that he serves on the speakers bureau for Athena Diagnostics and receives research funding from the National Ataxia Foundation.

Two different approaches to treating spinocerebellar ataxia type 1 – aerobic exercise or delivery of vascular endothelial growth factor – appeared to halt or slow the dysfunction of vulnerable cerebellar and brain stem cells in separate studies of a mouse model that closely mirrors the human disease.

The studies also shed light on how the poly-glutamine repeat mutation found in the AXTN1 gene of patients with spinocerebellar ataxia type 1 (SCA1) affects the transcription of particular genes that may contribute to the disease’s hallmark pathology of atrophy and loss of Purkinje neurons from the cerebellar cortex.

Patients with SCA1 most often initially experience problems with gait and balance, followed later by other motor difficulties, cognitive impairment, and sometimes sensory neuropathy, dystonia, and muscle atrophy and fasciculations.

Exercise Increased Life Span

The researchers, led by John D. Fryer, Ph.D., at Baylor College of Medicine, Houston, found that a regimen of relatively light exercise 5 days per week at an early age extended the life of mice with SCA1 by up to 6 weeks but did not improve their motor performance. This exercise led to a sustained increase in the level of epidermal growth factor (EGF) in the brain stem but not in the cerebellum (Science 2011;334:690-3).

The investigators also looked at how exercise affected the function of a transcriptional repressor protein called Capicua (Cic) that interacts with the ATXN1 gene’s protein product (ataxin 1) and lies downstream of EGF signaling.

Levels of Cic in SCA1 mice declined in the brainstem but not in the cerebellum after the exercise training period. Similarly, when brainstem neuronal cultures from SCA1 mice were exposed to EGF, levels of Cic declined. This suggested that a reduction of Cic itself might improve the survival of the SCA1 mice.

Further experiments showed that genetically reducing the level of Cic by 50% in SCA1 mice significantly improved their motor coordination, learning, and memory deficits; curbed the loss of Purkinje cells at 40 weeks of age; and extended their life span.

Genetic reduction of Cic improved motor coordination, according to Dr. Fryer and his coauthors. However, exercise on its own or in the amount undertaken in the first group of SCA1 mice did not improve motor coordination, judging from the observation that it lowered Cic levels only in the brainstem rather than in the cerebellum.

The investigators suggested that the deleterious effects of mutant ataxin 1 may be moderated by lower levels of Cic because the mutant protein appeared to cause a simultaneous increase or decrease in Cic’s transcriptional repression of certain genes. Based on these results, the researchers thought that therapeutics aimed at lowering Cic levels or disrupting the interaction between Cic and mutant ataxin 1 "could potentially ameliorate the disease."

Because the effect of exercise on life span lasted long after the mice stopped exercising, they suggested that "SCA1 individuals might benefit from an exercise program early in disease course." They described the exercise regimen as being "quite gentle," so they could not rule out "the possibility that more intense or longer-duration exercise could cause a sustained EGF increase and Cic decrease in the cerebellum that could lead to motor improvements."

Dr. S. H. Subramony, codirector of the ataxia clinic in the movement disorder center at the University of Florida, Gainesville, said in an interview that the study gives greater weight for the potential use of exercise training in neurodegenerative diseases. Exercise training has not been studied, to his knowledge, in individuals with SCA1. "I think we increasingly recognize that physical activity has numerous biochemical effects, many beneficial, including changes in gene transcription."

There is evolving evidence that suggests exercise in general increases life span, "so whether there is a specific effect of exercise on SCA1 pathogenesis or a general effect is not clear to me because they do not show a SCA1-specific effect in terms of motor performance and pathology in the cerebellum, but the parallel biochemical evidence suggests that it might" said Dr. Subramony, who was not involved with the study.

It remains to be clarified whether exercise needs to start before the onset of symptoms or can be begun after or how intense it needs to be, noted Dr. Subramony, who also is director of the neuromuscular division in the department of neurology at the university.

Another Growth Factor at Work in SCA1

Another study on SCA1 mice supports the notion that mutant ataxin 1 has a toxic gain of function in repressing the transcription of certain genes. Marija Cvetanovic, Ph.D., of Northwestern University, Chicago, found that another growth factor, vascular endothelial growth factor (VEGF), also is transcriptionally repressed by mutant ataxin 1.

Dr. Cvetanovic and her associates found that the expression of the gene for VEGF, an angiogenic and neurotrophic growth factor, was downregulated in the cerebellar Purkinje neurons of SCA1 mice before they showed any behavioral or pathologic signs of the disease. Mutant ataxin 1 directly repressed the expression of VEGF mRNA in the mice. The mutation of a site on the protein known to be crucial for its toxicity stopped its ability to repress the transcription of VEGF; this demonstrated that the repression of VEGF correlates with the in vivo toxicity of the mutant protein (Nat. Med. 2011;17:1445-7).

The researchers observed that VEGF repression induced hypoxia and also limited angiogenesis in the cerebellum of SCA1 mice by significantly decreasing cerebellar microvessel density and total vessel length. Inhibition of VEGF signaling in cerebellar neuronal cultures also decreased neurite length and increased cell death.

However, the genetic overexpression of VEGF beginning during embryonic development in SCA1 mice enhanced their motor performance at 13 weeks and 6 months of age and improved their cerebellar pathology. In other SCA1 mice, continuous intracerebroventricular delivery of VEGF after the onset of disease led to similar improvements.

"Our findings suggest a role for VEGF in SCA1 pathogenesis and indicate that restoring VEGF levels may be a potentially useful treatment in patients with SCA1," the researchers concluded.

When asked to comment on this research, Dr. Subramony called the VEGF study "elegant," but noted that studies of growth factors for other diseases have had generally disappointing results in translating murine data to humans. Another concern for translating the study to humans is in getting the molecule to enough of the affected area in human brains, which is less of a problem with very small mouse brains.

In addition, the literature suggests that mutant ataxin 1 causes dysregulation of many genes, not just VEGF, so "the possibility remains that just replacing VEGF may not rescue the disease in a more comprehensive manner because we know that a number of other genetic alterations take place in these tissues because of the mutation," he said.

"From a clinical perspective, it may be easier to translate the exercise study to humans because it is easier to put patients through an exercise program than to give them a novel molecule" such as VEGF, which to Dr. Subramony’s knowledge has not been studied in a human trial for any disease.

The exercise study was supported by grants from the National Institutes of Health (NIH). Dr. Fryer performed the research for the exercise study at Baylor, but he is now at the Mayo Clinic in Jacksonville, Fla. The VEGF study was supported by grants from the NIH, the U.S. National Organization for Rare Disorders, the U.S. Brain Research Foundation, and the U.S. National Ataxia Foundation. None of the authors of that study had relevant financial disclosures. Dr. Subramony said that he serves on the speakers bureau for Athena Diagnostics and receives research funding from the National Ataxia Foundation.

Two different approaches to treating spinocerebellar ataxia type 1 – aerobic exercise or delivery of vascular endothelial growth factor – appeared to halt or slow the dysfunction of vulnerable cerebellar and brain stem cells in separate studies of a mouse model that closely mirrors the human disease.

The studies also shed light on how the poly-glutamine repeat mutation found in the AXTN1 gene of patients with spinocerebellar ataxia type 1 (SCA1) affects the transcription of particular genes that may contribute to the disease’s hallmark pathology of atrophy and loss of Purkinje neurons from the cerebellar cortex.

Patients with SCA1 most often initially experience problems with gait and balance, followed later by other motor difficulties, cognitive impairment, and sometimes sensory neuropathy, dystonia, and muscle atrophy and fasciculations.

Exercise Increased Life Span

The researchers, led by John D. Fryer, Ph.D., at Baylor College of Medicine, Houston, found that a regimen of relatively light exercise 5 days per week at an early age extended the life of mice with SCA1 by up to 6 weeks but did not improve their motor performance. This exercise led to a sustained increase in the level of epidermal growth factor (EGF) in the brain stem but not in the cerebellum (Science 2011;334:690-3).

The investigators also looked at how exercise affected the function of a transcriptional repressor protein called Capicua (Cic) that interacts with the ATXN1 gene’s protein product (ataxin 1) and lies downstream of EGF signaling.

Levels of Cic in SCA1 mice declined in the brainstem but not in the cerebellum after the exercise training period. Similarly, when brainstem neuronal cultures from SCA1 mice were exposed to EGF, levels of Cic declined. This suggested that a reduction of Cic itself might improve the survival of the SCA1 mice.

Further experiments showed that genetically reducing the level of Cic by 50% in SCA1 mice significantly improved their motor coordination, learning, and memory deficits; curbed the loss of Purkinje cells at 40 weeks of age; and extended their life span.

Genetic reduction of Cic improved motor coordination, according to Dr. Fryer and his coauthors. However, exercise on its own or in the amount undertaken in the first group of SCA1 mice did not improve motor coordination, judging from the observation that it lowered Cic levels only in the brainstem rather than in the cerebellum.

The investigators suggested that the deleterious effects of mutant ataxin 1 may be moderated by lower levels of Cic because the mutant protein appeared to cause a simultaneous increase or decrease in Cic’s transcriptional repression of certain genes. Based on these results, the researchers thought that therapeutics aimed at lowering Cic levels or disrupting the interaction between Cic and mutant ataxin 1 "could potentially ameliorate the disease."

Because the effect of exercise on life span lasted long after the mice stopped exercising, they suggested that "SCA1 individuals might benefit from an exercise program early in disease course." They described the exercise regimen as being "quite gentle," so they could not rule out "the possibility that more intense or longer-duration exercise could cause a sustained EGF increase and Cic decrease in the cerebellum that could lead to motor improvements."

Dr. S. H. Subramony, codirector of the ataxia clinic in the movement disorder center at the University of Florida, Gainesville, said in an interview that the study gives greater weight for the potential use of exercise training in neurodegenerative diseases. Exercise training has not been studied, to his knowledge, in individuals with SCA1. "I think we increasingly recognize that physical activity has numerous biochemical effects, many beneficial, including changes in gene transcription."

There is evolving evidence that suggests exercise in general increases life span, "so whether there is a specific effect of exercise on SCA1 pathogenesis or a general effect is not clear to me because they do not show a SCA1-specific effect in terms of motor performance and pathology in the cerebellum, but the parallel biochemical evidence suggests that it might" said Dr. Subramony, who was not involved with the study.

It remains to be clarified whether exercise needs to start before the onset of symptoms or can be begun after or how intense it needs to be, noted Dr. Subramony, who also is director of the neuromuscular division in the department of neurology at the university.

Another Growth Factor at Work in SCA1

Another study on SCA1 mice supports the notion that mutant ataxin 1 has a toxic gain of function in repressing the transcription of certain genes. Marija Cvetanovic, Ph.D., of Northwestern University, Chicago, found that another growth factor, vascular endothelial growth factor (VEGF), also is transcriptionally repressed by mutant ataxin 1.

Dr. Cvetanovic and her associates found that the expression of the gene for VEGF, an angiogenic and neurotrophic growth factor, was downregulated in the cerebellar Purkinje neurons of SCA1 mice before they showed any behavioral or pathologic signs of the disease. Mutant ataxin 1 directly repressed the expression of VEGF mRNA in the mice. The mutation of a site on the protein known to be crucial for its toxicity stopped its ability to repress the transcription of VEGF; this demonstrated that the repression of VEGF correlates with the in vivo toxicity of the mutant protein (Nat. Med. 2011;17:1445-7).

The researchers observed that VEGF repression induced hypoxia and also limited angiogenesis in the cerebellum of SCA1 mice by significantly decreasing cerebellar microvessel density and total vessel length. Inhibition of VEGF signaling in cerebellar neuronal cultures also decreased neurite length and increased cell death.

However, the genetic overexpression of VEGF beginning during embryonic development in SCA1 mice enhanced their motor performance at 13 weeks and 6 months of age and improved their cerebellar pathology. In other SCA1 mice, continuous intracerebroventricular delivery of VEGF after the onset of disease led to similar improvements.

"Our findings suggest a role for VEGF in SCA1 pathogenesis and indicate that restoring VEGF levels may be a potentially useful treatment in patients with SCA1," the researchers concluded.

When asked to comment on this research, Dr. Subramony called the VEGF study "elegant," but noted that studies of growth factors for other diseases have had generally disappointing results in translating murine data to humans. Another concern for translating the study to humans is in getting the molecule to enough of the affected area in human brains, which is less of a problem with very small mouse brains.

In addition, the literature suggests that mutant ataxin 1 causes dysregulation of many genes, not just VEGF, so "the possibility remains that just replacing VEGF may not rescue the disease in a more comprehensive manner because we know that a number of other genetic alterations take place in these tissues because of the mutation," he said.

"From a clinical perspective, it may be easier to translate the exercise study to humans because it is easier to put patients through an exercise program than to give them a novel molecule" such as VEGF, which to Dr. Subramony’s knowledge has not been studied in a human trial for any disease.

The exercise study was supported by grants from the National Institutes of Health (NIH). Dr. Fryer performed the research for the exercise study at Baylor, but he is now at the Mayo Clinic in Jacksonville, Fla. The VEGF study was supported by grants from the NIH, the U.S. National Organization for Rare Disorders, the U.S. Brain Research Foundation, and the U.S. National Ataxia Foundation. None of the authors of that study had relevant financial disclosures. Dr. Subramony said that he serves on the speakers bureau for Athena Diagnostics and receives research funding from the National Ataxia Foundation.