Spinocerebellar ataxias: an update.
OBJECTIVE
Here we discuss recent advances regarding the molecular genetic basis of dominantly inherited ataxias.


RESULTS
Important recent observations include insights into the mechanisms by which expanded polyglutamine causes cerebellar degeneration; new findings regarding how noncoding expansions may cause disease; the discovery that conventional (i.e. nonrepeat) mutations underlie recently identified ataxias; and growing recognition that multiple biological pathways, when perturbed, can cause cerebellar degeneration.


CONCLUSIONS
The dominant ataxias, also known as spinocerebellar ataxias, continue to grow in number. Here we review the major categories of spinocerebellar ataxias: expanded polyglutamine ataxias; noncoding repeat ataxias; and ataxias caused by conventional mutations. After discussing features shared by these disorders, we present recent evidence supporting a toxic protein mechanism for the polyglutamine spinocerebellar ataxias and the recognition that both protein misfolding and perturbations in nuclear events represent key events in pathogenesis. Less is known about pathogenic mechanisms in spinocerebellar ataxias due to noncoding repeats, though a toxic RNA effect remains possible. Newly discovered, conventional mutations in spinocerebellar ataxias suggest a wide range of biological pathways can be disrupted to cause progressive ataxia. Finally, we discuss how new mechanistic insights can drive the push toward preventive treatment.
Soong
Bing-wen
BW
Department of Neurology, National Yang-Ming University School of Medicine, The Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
Paulson
Henry L
HL
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D017510:Protein Folding; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D020754:Spinocerebellar Ataxias / Q000145:classification / Q000235:genetics / Q000503:physiopathology / Q000628:therapy
C415906:ATXN8OS gene product, human; D009419:Nerve Tissue Proteins; D010455:Peptides; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C097188:polyglutamine