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Neurology Today:
doi: 10.1097/01.NT.0000333578.34727.35
Article

Early Developmental Effects Affect Susceptibility to Late‐Onset Ataxia

ROBINSON, RICHARD

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CHICAGO—Basic research in spinocerebellar ataxia 1 (SCA1) shows that early development affects susceptibility to late-onset neurodegenerative disease, and the effects of SCA1 may be reversible if treated early enough, according to Harry Orr, PhD. Dr. Orr, director of the Institute of the Human Genetics at the University of Minnesota School of Medicine in Minneapolis, described the latest advances during the Frontiers in Clinical Neuroscience plenary at the AAN annual meeting here.

SCA1 is an autosomal dominant, late-onset, fatal neurodegenerative disorder. The ataxia is attributed primarily to loss of Purkinje cells in the cerebellar cortex, as well as neurons in the dentate nucleus and red nucleus. The disorder affects only one in 100,000 people, but insights from SCA1 research have implications for more than SCA1, Dr. Orr said.

The causative mutation is a CAG expansion in the SCA1 gene, leading to an expanded polyglutamine tract in the ataxin-1 protein. Ataxin-1 is an 800-amino acid protein with a normal polyglutamine tract of six to 44 glutamines. The mutant version contains 39 to 83 glutamines.

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WORK IN THE MOUSE MODEL

To try to understand how the mutation leads to disease, Dr. Orr, with his long-time collaborator Huda Zoghbi, MD, turned to a mouse model. Simple overexpression of SCA1 in the mouse reproduced both the human pathology and important aspects of the clinical phenotype.

But to what extent is the damage reversible? This question can be answered by using a “conditional mutant,” in which the mutant gene is equipped with an on-off switch, flipped by exposure to an antibiotic.

Dr. Orr's group found that mice expressing the mutant SCA1 gene from conception could completely recover, both behaviorally and morphologically, if the gene was switched off within six weeks after birth (adolescence for a mouse), when there are already signs of atrophy of the dendritic tree and ataxia. Delaying the rescue until 12 weeks led to only partial motor recovery, but complete recovery morphologically, with restored thickness of the molecular layer of the Purkinje cell dendrites. Rescue at 32 weeks led to only partial morphological recovery. At all stages, the mutant protein was readily cleared from within the cells.

“The really encouraging result from a therapeutic standpoint is that, even at late stages, these Purkinje cells show dramatic evidence of some ability to be repaired. We are not sure if the effect at different stages reflects an accumulation of damage, or whether older neurons are just less able to recover than younger ones,” he said

Surprisingly for a late-onset disease, the mutant protein seems to have its most important effect early in the mouse's life. A clue that this might be so came from the discovery that one line of mutant mice had a more severe disease despite having far less protein in adults than other mutants did. The key difference was that they began producing it in significant quantities at day two rather than day 10, as the others did.

Using the conditional mutants again, the team found that shutting the gene off early in postnatal development protected the mice. “The bottom line is that if we keep the gene off during this critical period of cerebellar development, we have a substantial effect on pathogenesis,” Dr. Orr said. “The animals have a substantially increased resistance to the effects of the mutant protein” when they are later exposed to it.

The basis of this developmental susceptibility, their research has shown, is the interaction between the mutant protein and a transcriptional complex. The complex is important for Purkinje cell development and especially for elaboration of the dendritic tree, which occurs during the first three weeks of postnatal life. “We are intrigued by the possibility that this might suggest a link in general between neuronal development and subsequent susceptibility of neurons to stress in the adult,” Dr. Orr said.

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AN IMPORTANT MOLECULAR SWITCH

A longstanding question in the polyglutamine diseases is whether the disease arises from the insoluble aggregates of excess protein seen in the brains of both humans and disease mice or whether toxicity arises from a soluble form of the protein.

“Over the years, our results have shown that the toxicity of mutant ataxin-1 is due to properties of the soluble protein, and its interactions with other normal cellular partners in the cell, and not to the insoluble accumulations one sees pathologically,” Dr. Orr said. “The flip side of this is that we think the normal function and biochemistry of this protein is intimately linked to the pathogenic process of the disease, and somehow the polyglutamine expansion corrupts this normal biology. We think this is going to turn out to be one of the more exciting areas, in terms of therapeutic strategies.”

In particular, his lab has shown that phosphorylation at a specific site on ataxin-1 is important for pathogenesis. Phosphorylation is a cellular technique by which protein function is regulated, typically turning a protein on or off in response to events in the cell. Preventing phosphorylation dramatically reduces the ability of the mutant protein to cause disease — these mice are pathologically and behaviorally normal, even late in life, “suggesting that phosphorylation is another component that is important to disease,” along with polyglutamine expansion, he said.

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ROLE OF RBM17

Dr. Orr's group discovered a protein, RBM17, which interacts more readily with ataxin-1 in its expanded, phosphorylated form. RBM17 is involved in splicing RNA transcripts to form mature messenger RNA, though what role, if any, that may play in SCA1 is unknown. Normal-length ataxin-1 can be made toxic simply by altering the phosphorylation site so the protein is switched permanently “on” —Purkinje cells show the same level of dendritic atrophy, even though their polyglutamine tract is entirely normal.

“Both neurologically and pathologically, this single change converts a wild-type allele into what appears to be a pathogenic allele,” Dr. Orr said.

“This suggests that phosphorylation is a strong target for therapeutic development,” he said, a process currently under way.

“This novel discovery, that SCA1 exerts a deleterious effect during development, fits into our general notion that the effects of some mutations may occur as the brain is laid down,” said Stephan Pulst, MD, chair of the Academy's Science Committee and chairman of neurology at the University of Utah in Salt Lake City.

Whether this pattern is seen in other polyglutamine diseases remains to be discovered, he said, “but I would not be surprised if we find evidence for that.” He noted that subtle effects can be seen in “preclinical” individuals with several forms of late-onset neurodegenerative diseases, and evidence is accumulating that developmental events may influence susceptibility to Alzheimer disease as well.

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ON POLYGLUTAMINE DISEASES

One of the eight other known polyglutamine diseases is Huntington disease. On the molecular level they have little in common besides the type of mutation — the genes belong to no common family, and the proteins affected have no features in common except polyglutamine domains. Each disease affects a different brain region or set of cells, and clinical manifestations differ as well. But each causes a late-onset neurodegenerative disease, with onset and severity correlated to length of the polyglutamine tract.

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ARTICLE IN BRIEF

Dr. Harry Orr reported that early development affects susceptibility to late-onset neurodegenerative disease, and the effects of spinocerebellar ataxia 1 may be reversible if treated early enough.

©2008 American Academy of Neurology

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