Abstract
Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine-encoding CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by progressive motor deficits, cognitive decline, and mood changes including anxiety and depression, with longer number of repeats correlating with worse disease outcomes. While mouse models have been very useful in understanding etiology of ataxia and cognitive decline, our understanding of mood symptoms in SCA1 has lagged. It remains unclear whether anxiety or depression stem from an underlying brain pathology or as a consequence of living with an untreatable and lethal disease. To increase our understanding of the etiology of SCA1 mood alterations, we used the elevated-plus maze, sucrose preference and forced swim tests to assess mood in four different mouse lines. We found that SCA1 knock-in mice exhibit increased anxiety that correlated with the length of CAG repeats, supporting the idea that underlying brain pathology contributes to SCA1-like anxiety. Additionally, our results support the concept that increased anxiety is caused by non-cerebellar pathology, as Purkinje cell specific SCA1 transgenic mice exhibit decreased anxiety-like behavior. Regarding the molecular mechanism, partial loss of ATXN1 may play a role in anxiety, based on our results for Atxn1 haploinsufficient and null mice.
Highlights
Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine-encoding CAG repeats in the Ataxin-1 (ATXN1) gene
SCA1 is caused by an abnormal expansion of CAG repeats in the coding region of Ataxin-1 (ATXN1) gene, which leads to an expanded polyglutamine tract in the protein A TXN11
To investigate the contribution of cerebellar pathology to the mood alterations caused by mutant ATXN1, we examined an SCA1 transgenic mouse model, ATXN1[82Q] mice, which overexpress mutant ATXN1[82Q] only in cerebellar Purkinje cells under the control of the Purkinje cell protein 2 (Pcp2) p romoter[28]
Summary
Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine-encoding CAG repeats in the Ataxin-1 (ATXN1) gene. While mouse models have been very useful in understanding etiology of ataxia and cognitive decline, our understanding of mood symptoms in SCA1 has lagged It remains unclear whether anxiety or depression stem from an underlying brain pathology or as a consequence of living with an untreatable and lethal disease. Very little is known about the etiology of mood symptoms in SCA1 It is not clear whether anxiety and depression stem from the knowledge that patients suffer from untreatable, progressively debilitating and fatal disease, or is caused by underlying pathology[6,8,19]. In addition to its well-known role in motor movement, cerebellar contribution to cognition and mood has been increasingly
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