Research ArticleNeurodegenerative Disease

An miRNA-mediated therapy for SCA6 blocks IRES-driven translation of the CACNA1A second cistron

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Science Translational Medicine  13 Jul 2016:
Vol. 8, Issue 347, pp. 347ra94
DOI: 10.1126/scitranslmed.aaf5660

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Blunting the sharp end of the spear

Selectively turning off disease genes without disrupting other processes has been a growing goal of genetic research. In a new study, Miyazaki et al. work with a gene that expresses two proteins, a calcium channel, necessary for life, and a regulatory protein, α1ACT, which when mutated causes a form of ataxia called SCA6. These investigators figured out how to block expression of the disease protein without affecting the calcium channel using a small sequence of RNA called miRNA. They then used a viral vector to deliver this miRNA to mice engineered to develop a severe form of SCA6 and successfully prevented the disease.


Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by slowly progressive ataxia and Purkinje cell degeneration. SCA6 is caused by a polyglutamine repeat expansion within a second CACNA1A gene product, α1ACT. α1ACT expression is under the control of an internal ribosomal entry site (IRES) present within the CACNA1A coding region. Whereas SCA6 allele knock-in mice show indistinguishable phenotypes from wild-type littermates, expression of SCA6-associated α1ACT (α1ACTSCA6) driven by a Purkinje cell–specific promoter in mice produces slowly progressive ataxia and cerebellar atrophy. We developed an early-onset SCA6 mouse model using an adeno-associated virus (AAV)–based gene delivery system to ectopically express CACNA1A IRES–driven α1ACTSCA6 to test the potential of CACNA1A IRES–targeting therapies. Mice expressing AAV9-mediated CACNA1A IRES–driven α1ACTSCA6 exhibited early-onset ataxia, motor deficits, and Purkinje cell degeneration. We identified miR-3191-5p as a microRNA (miRNA) that targeted CACNA1A IRES and preferentially inhibited the CACNA1A IRES–driven translation of α1ACT in an Argonaute 4 (Ago4)–dependent manner. We found that eukaryotic initiation factors (eIFs), eIF4AII and eIF4GII, interacted with the CACNA1A IRES to enhance α1ACT translation. Ago4-bound miR-3191-5p blocked the interaction of eIF4AII and eIF4GII with the CACNA1A IRES, attenuating IRES-driven α1ACT translation. Furthermore, AAV9-mediated delivery of miR-3191-5p protected mice from the ataxia, motor deficits, and Purkinje cell degeneration caused by CACNA1A IRES–driven α1ACTSCA6. We have established proof of principle that viral delivery of an miRNA can rescue a disease phenotype through modulation of cellular IRES activity in a mouse model.

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