Age-associated neurodegeneration is often caused by the accumulation of misfolded or mutant proteins. Many neurodegenerative disorders result from CAG/polyglutamine tract expansions, which produce misfolded proteins that are toxic through mechanisms that are incompletely understood. Nine neurological diseases are known to be caused by expansions of CAG repeats, including Kennedy disease, where a repeat expansion in the androgen receptor (AR) causes hormone-dependent lower motor neuron loss and skeletal muscle pathology.
The authors recently generated a mouse model of Kennedy disease using gene targeting to exchange much of the coding region of the mouse androgen receptor (Ar) exon 1 with human sequence containing an expanded CAG repeat that is associated with disease (AR113Q mice). Mice expressing the expanded glutamine AR develop androgen-dependent neuromuscular and systemic disease that models changes in Kennedy disease patients, including skeletal muscle pathology exhibiting evidence of both denervation and myopathy. The mechanism of disease is unknown, and there are no effective treatments available for patients with Kennedy disease or related polyglutamine tract expansion disorders.
Here, using AR113Q mice, the authors identify changes in RNA splicing that decrease the expression of the skeletal muscle chloride channel CLC-1, which is needed to maintain normal membrane potentials in cells. Altered splicing of Clcn1 RNAs in AR113Q skeletal muscle induces changes similar to those in myotonic dystrophy (DM), a multisystem disorder that is caused by CUG or CCUG repeat expansions in noncoding regions that are pathogenic at the RNA level. RNA missplicing in AR113Q mice also increases the expression of CUGBP1, an RNA-binding protein implicated in DM pathogenesis. CUGBP1 expression is similarly increased by surgical denervation of wild-type muscle but is not sufficient to cause changes in Clcn1 RNA splicing. Thus, the cell-autonomous mechanisms triggered by AR113Q protein toxicity in muscle result in RNA splicing, which may contribute to the symptoms associated with Kennedy disease and similar neurodegenerative diseases.
This work identifies a mechanism augmenting cellular dysfunction in Kennedy disease, whereby the mutant protein alters RNA splicing in a hormone- and glutamine length-dependent manner. The authors suggest that altered RNA splicing may target androgen-regulated genes and amplify the effects of the expanded glutamine tract on AR-mediated gene transcription. These findings support the emerging concept that shared mechanisms exist among repeat expansion diseases, and raise the possibility that changes in RNA processing may contribute to cellular dysfunction in other polyglutamine neurodegenerative disorders.
