Human ataxias: a genetic dissection of inositol triphosphate receptor ( ITPR1 )-dependent signaling

• Published in: Trends in neurosciences (Regular ed.) 2010-05, Vol.33 (5), p.211-219
• Main Authors: Schorge, Stephanie, van de Leemput, Joyce, Singleton, Andrew, Houlden, Henry, Hardy, John
• Format: Article
• Language: English
• Subjects: Animals; Ataxia; Biological and medical sciences; Brain; Calcium - metabolism; Calcium Channels, N-Type - genetics; Cerebellar Ataxia - genetics; Cerebellar Ataxia - pathology; Fundamental and applied biological sciences. Psychology; General aspects. Models. Methods; Genes; Genetics; Glutamic Acid - metabolism; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Inositol 1,4,5-Trisphosphate Receptors - genetics; Medical sciences; Models, Biological; Mutation; Mutation - genetics; Nervous system (semeiology, syndromes); Neurology; Peptides - genetics; Potassium Channels - genetics; Proteins; Purkinje Cells - metabolism; Signal Transduction - genetics; Vertebrates: nervous system and sense organs
• ISSN: 0166-2236; 1878-108X
• DOI: 10.1016/j.tins.2010.02.005

A persistent mystery about the ataxias has been why mutations in genes – many of which are expressed widely in the brain – primarily cause ataxia, and not, for example, epilepsy or dementia. Why should a polyglutamine stretch in the TATA-binding protein (that is important in all cells) particularly disrupt cerebellar coordination? We propose that advances in the genetics of cerebellar ataxias suggest a rational hypothesis for how so many different genes lead to predominantly cerebellar defects. We argue that the unifying feature of many genes involved in cerebellar ataxias is their impact on the signaling protein ITPR1 (inositiol 1,4,5-triphosphate receptor type 1), that underlies coincidence detection in Purkinje cells and could play an important role in cerebellar coordination.