ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism

Abstract

Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity.

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1

“…Finally, we found that viral overexpression of Cic in the nodular zone recapitulated the firing abnormalities seen in the anterior cerebellum and also accelerated nodular zone neurodegeneration. Our findings underscore the central role for Cic in SCA1 cerebellar pathophysiology (Rousseaux et al, 2018). These findings provide important insights regarding Purkinje neuron vulnerability in SCA1 and elevate these channels as important targets for the development of disease-modifying therapy.…”

“…Cic forms a native complex with ATXN1 that is essential for SCA1 pathogenesis (Fryer et al, 2011;Lam et al, 2006;Rousseaux et al, 2018). While significant progress has been made in understanding the ATXN1/Cic complex, including a validated partial crystal structure (Kim et al, 2013), much less is known about the mechanisms by which this complex drives Purkinje neuron degeneration.…”

“…This conclusion is supported by a transgenic model of SCA1 with expression of ATXN1 with 82 CAG repeats (ATXN1[82Q]) restricted to Purkinje neurons, resulting in prominent Purkinje neuron degeneration and motor impairment (Burright et al, 1995). It is well-understood that dysregulation of gene expression is central to SCA1 pathogenesis (Klement et al, 1998;Rousseaux et al, 2018), but the key disease-associated genes underlying Purkinje neuron degeneration are not well understood.…”

Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors

“…Our studies, which primarily focused on early events, did not systematically address questions of neuronal maturation (although some of our in vitro findings are consistent with a neuronal maturation defect). Together, however, the cumulative data point to important roles for Cic in both initial specification as well as maintenance of neurons -highlighting the need for future work to define the complex neuronal dependencies on Cic, not only in the forebrain but also in the cerebellum where Cic pathology has also been implicated (38) (39).…”

A Guided Network Propagation Approach to Identify Disease Genes that Combines Prior and New Information

“…Among these novel predictions for GBM are ATXN1, SMURF1, and CCR3, all of which have been recently suggested to play a role in cancers [45][46][47] and are each mutated in less than 5% of the samples. ATXN1 is a chromatin-binding factor that plays a critical role in the development of spinocerebellar ataxia, a neurodegenerative disorder [48], and mutants of ATXN1 have been found to stimulate the proliferation of cerebellar stem cells in mice [49]. This is a promising gene for further investigation because glioblastoma is a cancer that usually starts in the cerebrum and the potential role of ATXN1 in tumorigenesis has only recently been suggested [45].…”