RORα-Mediated Purkinje Cell Development Determines Disease Severity in Adult SCA1 Mice

Abstract

Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited, typically adult onset, polyglutamine neurodegenerative diseases. To examine whether development impacts SCA1, we used a conditional transgenic mouse model of SCA1 to delay the postnatal expression of mutant ATXN1 until after completion of cerebellar development. Delayed postnatal expression of mutant ATXN1 led to a substantial reduction in severity of disease in adults in comparison with early postnatal gene expression. This was linked to a destabilization of RORalpha, a transcription factor critical for cerebellar development. In SCA1 mice, there was a depletion of RORalpha and a reduction in expression of genes controlled by RORalpha. Partial loss of RORalpha enhanced mutant ATXN1 pathogenicity. Additionally, evidence points to the existence of a complex containing ATXN1, RORalpha, and the RORalpha coactivator Tip60. These studies indicate RORalpha and Tip60 have a role in SCA1 and suggest a mechanism by which compromising cerebellar development contributes to severity of neurodegeneration in an adult.

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

“…In our study, the complete rescue of embryonic lethality by administering DOX to the mothers before mating demonstrates the efficiency of DOX-dependent activation of tTA. Moreover, the embryonic phenotype observed in this SCA1 model indicates that expression of mutant ATAXIN1 during embryonic development increases the severity of the disease, as reported recently by others (Serra et al, 2006). The first appearance of ATAXIN1 mRNA is detected in 2-week-old DTg mice.…”

“…To investigate the cellular pathways that influence disease progression, SCA1 transgenic mice have been crossed with either transgenic mice or mice that are deficient in genes involved specifically in protein degradation or stress responses (Cummings et al, 1999;Shahbazian et al, 2001;Cummings et al, 2001;Okuda et al, 2003). Recently, it has been demonstrated that blocking the expression of mutant ATAXIN1 in a conditional mouse model of SCA1 modifies the progression of the disease (Zu et al, 2004;Serra et al, 2006). The majority of these models are somewhat limited because they involve the expression of the polyQ tract mainly in cerebellar Purkinje cells.…”

Aβ40 promotes neuronal cell fate in neural progenitor cells

“…27 Disturbed neurogenesis during early development can result in neurodegeneration in adulthood as exemplified by the spinocerebellar ataxia type 1 mouse model. 37 Thus, the effect of Ab40 and Ab42 on prenatal cerebral NPCs may reflect their physiological functions during development. The possibility that a perturbation of early neural development could contribute to adult onset of AD may be investigated in animal models in vivo.…”

Cerebellar development and disease

“…An intriguing recent paper demonstrates that compromising Purkinje cell development, by expressing a toxic transgene early in development, contributes to the severity of the neurodegeneration in adult mice [68]. This data suggests an overlap between development and degeneration, and that the eventual timing of the onset of degeneration is actually determined during pre-natal life.…”