Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a polyglutamine (CAG) expansion sequence on the Ataxin-1 (ATXN1) gene [1]. The normal allele contains 6-42 CAG repeats while the disease allele contains 39-82 CAG repeats [1]. The mutant morphology is characterized by neuronal loss, in particular, the loss of Purkinje neurons of the cerebellum, thinning of the cerebellum molecular layer and dendritic atrophy [1]. Patients with SCA1 experience progressive loss of motor coordination and function, unstable gait, and dysarthric speech [1]. At the genetic and protein level, many factors have been implicated in the onset, development, regulation and severity of the disease. These factors include the size of the polyglutamine repeat, the AXH domain, the role of lysine residue 772 in nuclear localization and the phosphorylation of serine residue 776 [1]. At the protein level, the ataxin-1 mutant protein is known to interact with transcriptional regulators such as Capicua and with RNA-splicing factors such as RBM17 [2]. Like all neurodegenerative diseases, there is currently no cure. However, multiple potential therapeutic methods are under investigation and show promising implications for clinical implementation including RNAi suppression of the mutant gene and stem cell treatments.

1. Orr, HT. SCA1 – Phosphorylation, a regulator of ataxin-1 function and pathogenesis. Prog Neurobiol. 99: 179-185 (2012).
2. Lim, J et al. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature. 452: 713-718 (2008).

SCA1 Gene and Protein Biochemistry

main article: SCA1 Gene and Protein Biochemistry
author: Monica Akula

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This diagram depicts the progressive degeneration of Purkinje cells
in the cerebellum of transgenic mice with SCA1 over a 40 week period [3].

Mutations in the ATXN1 gene have long been known to cause Spinocerebellar Ataxia I (SCA1), a neurodegenerative disease that particularly affects Purkinje neurons in the cerebellum, leading to motor function problems [1]. Not only is the gene itself responsible for expression of neuropathology, but the subsequently transcribed mRNA also appears to play a role in expression of symptoms, as a result of the formation of secondary structures [2]. This transcript, when translated into the Ataxin-1 protein, causes protein aggregates to form because of certain domains and amino acid residues present in it [3]. It is important to study the gene and protein biochemistry of ATXN1 because it offers insights into treatment options for SCA1.

1. Burright, E., Clark HB., Servadio, A., Matilla, T., Fededrson, R. M., Yunis, W. S., Duvick, L. A., Zoghbi, H. Y. & Orr, H. T. SCA1 transgenic mice: A model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell, 82, 937-948 (1995).
2. Sobczak, K. & Krzyzosiak W. J. Imperfect CAG Repeats Form Diverse Structures in SCA1 Transcripts. J. Biol. Chem. 279, 41563 – 41572 (2004).
3. Orr, HT. SCA1 – Phosphorylation, a regulator of ataxin-1 function and pathogenesis. Prog. Neurobiol. 99, 179-185 (2012).

Therapeutic Strategies for SCA1

main article: Therapeutic Strategies for SCA1
author: Heting Yu

SCA1 transgenic mice
Rotarod performance is used as a measure of ataxia severity [2]

Current research on SCA1 presents evidence on several features of the mutant ataxin-1 protein (ATXN1) that are critical in determining disease severity, toxicity and neuropathology. These features are an expanded polyglutamine (polyQ) tract, a nuclear localization signal (NLS), an AXH domain for protein-protein interactions, and the phosphorylation of Serine residue 776 [1]. Similar to other polyglutamine disorders, mutant ATXN1 also forms protein aggregates, and its toxicity is mediated by a gain-of-function mechanism [1]. Many of these pathological and characteristic features can be targeted by various therapeutic strategies through the use of transgenic and knock-in mouse models. Potential treatments include mutant gene silencing via RNAi mechanisms, mesenchymal stem cell therapy, interfering with mutant protein interactions, increasing mutant ATXN1 degradation, and using protein kinase inhibitors.

1. Orr, HT. SCA1 – Phosphorylation, a regulator of ataxin-1 function and pathogenesis. Prog Neurobiol. 99: 179-185 (2012).
2. Scientific Video TV (uploaded Nov. 9, 2013). SCA1 Mouse on Rotarod. Retrieved March 27, 2014 from http://www.youtube.com/watch?v=DkE1QVLP9sk.

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