Genetically modified rodent models of SCA17

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Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease caused by expansion of CAA/CAG repeats that are translated to an expanded polyglutamine repeat in TATA‐box binding protein (TBP). Based on Harding's classification (Whaley et al., 2011), SCA17 belongs to type 1 ADCA (autosomal dominant cerebellar ataxia/spinocerebellar ataxia), featuring cerebellar syndrome and other neurologic symptoms such as pyramidal and extrapyramidal signs, ophthalmoplegia, and dementia. Type 1 ADCA is divided into 21 subtypes, including SCA1‐SCA4, SCA8, SCA10, SCA12‐SCA14, SCA15/16, SCA17‐SCA23, SCA25, SCA27, SCA28, and dentatorubral pallidoluysian atrophy (Whaley et al., 2011).
In 1999, an expanded CAG repeat in the TBP gene was identified in a 14‐year‐old Japanese female patient with progressive ataxia and intellectual deterioration (Koide et al., 1999). In 2001, Nakamura et al. verified this abnormal CAG expansion in the TBP gene in four Japanese pedigrees with SCA17 (Nakamura et al., 2001). Since then, more patients with SCA17 with complex clinical features and neuropathological changes were found to have this CAG repeat expansion in the TBP gene (Fujigasaki et al., 2001; Zuhlke et al., 2001; Silveira et al., 2002; Rolfs et al., 2003; Bauer et al., 2004; Bruni et al., 2004; Lasek et al., 2006; Toyoshima et al., 2004).
The normal repeat number in the TBP gene varies from 25 to 40, reduced‐penetrance alleles range from 41 to 48, and full‐penetrance alleles carry more than 48 CAG/CAA repeats that can lead to SCA17. The configuration of the repeat sequence in TBP is (CAG)3 (CAA)3 (CAG)x CAA CAG CAA (CAG)y CAA CAG in which X ranges from 7 to 11 and Y ranges from 9 to 21 (Fig. 1). This domain is divided into five segments, in which the most frequent expansion occurs in domain IV (van Roon‐Mom et al., 2005) and the CAA CAG CAA interruption (domain III) works as a stabilizer for transmission between generations (Maltecca et al., 2003; Gao et al., 2008). Therefore, depending on the absence or presence of domain III, two subtypes of TBP gene mutation were determined: type I with domain III, and type II without domain III. Type I is more prevalent than type II (Gao et al., 2008), and type II features unstable transmission, leading to intergenerational instability in German and Italian families (Maltecca et al., 2003). As a general transcriptional factor, TBP protein works as a critical part of the preinitiation complex with polymerase II and other molecules, which bind to the TATA box to initiate transcription (Roeder, 1991; Gostout et al., 1993).
The clinical features of SCA17 are broad and variable. Patients with SCA17 present a variety of prominent symptoms in an age‐dependent manner. Like other polyQ diseases, most SCA17 cases show late‐onset and progressive symptoms. The most frequently observed clinical symptom is cerebellar ataxia, and other clinical symptoms include dementia, psychiatric symptoms, pyramidal signs, abnormal movements, parkinsonism, and epilepsy (Koide et al., 1999; Rolfs et al., 2003; Bruni et al., 2004; Stevanin and Brice, 2008). Variable clinical features overlap with those in other neurodegenerative diseases, especially Huntington disease, leading to difficulty in clinical diagnosis of SCA17 (Stevanin and Brice, 2008).
The neuropathological lesions are present mainly in the cerebellum and cortex, with mild alteration in the brain stem, which is consistent with the most frequently observed ataxia symptoms. Within the cerebellum, Purkinje cells show the most severe degeneration, while mild neuronal loss has been observed in the dentate nucleus and granular layers (Stevanin and Brice, 2008). In the cerebral cortex, abnormal arborization of neuronal dendrites and spongiosis are present in the motor cortex and visual areas (Fujigasaki et al., 2001; Bruni et al., 2004; Toyoshima et al., 2004).
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