Non‐invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by 1H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1154Q/2Q line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1154Q/2Q mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39 weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1154Q/2Q mice displayed very mild cerebellar pathology even at 39 weeks, however, were distinguished from wild types by MRS starting at 6 weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12 weeks in Sca1154Q/2Q mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology.

Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology

“…3). Unlike prior studies (Emir et al, 2013; Öz et al, 2010b; Öz et al, 2011b), taurine levels in the WT group were lower, rather than higher, than the condSCA1 [ 82Q ] mice. The reason for this difference is unclear, but may be related to a different osmolytic status of the tTA mice than the FVB strain, which we had used as the background control for the transgenic SCA1 model in the past (Öz et al, 2010b; Öz et al, 2011b).…”

“…Based on all our MRS studies in SCA1 mice so far, the earliest changes are observed in taurine, glutamine, tCr and tCho, indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism (Emir et al, 2013). These are followed by changes in the neuronal viability marker NAA, the putative gliosis marker Ins and later by the neurotransmitter glutamate (Öz et al, 2010b).…”

“…Remarkably, the same neurochemicals, namely N -acetylaspartate (NAA), myo -inositol (Ins) and glutamate, also distinguished patients with SCA1 from controls and correlated with scores on a standardized ataxia rating scale (Öz et al, 2010a). We further showed that abnormal neurochemical levels reverse towards wild-type (WT) levels upon suppression of transgene expression in a conditional SCA1 [ 82Q ] line (Öz et al, 2011b) and that early neurochemical changes are detectable even in the absence of overt pathology in a knock-in model of SCA1 (Emir et al, 2013). Together these data demonstrated the potential of MRS-measured neurochemical levels as robust biomarkers of progressive neurodegeneration and its reversal in SCA1.…”

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

“…This reduction in total NAA levels directly correlates with SCA1 patients' ataxia scores and similar changes have also been observed in SCA1 mouse models. Notably, these changes have been demonstrated to be dependent on the expression of mutant ATXN1 protein and its deletion in conditional SCA1 models rescues those deficits (Emir et al, 2013;Guerrini et al, 2004;Oz et al, 2010). Interestingly, N-acetylaspartate (NAA) is synthesized by mitochondria and is a neuron-specific metabolite.…”

Proceedings of the workshop on Cerebellum, Basal Ganglia and Cortical Connections Unmasked in Health and Disorder Held in Brno, Czech Republic, October 17th, 2013

“…Namely, upon suppression of transgene expression in this model, both the cerebellar pathology and abnormal neurochemical levels returned towards normal [Oz, Vollmers, et al, 2011]. Finally, studies with a knock-in SCA1 model that displays milder cerebellar pathology than the transgenic line used in prior studies showed that neurochemical alterations can be detected prior to overt pathology in SCA1 [Emir et al, 2013]. To summarize, 1) 1 H MRS detects parallel neurochemical alterations in patients with SCA1 and SCA1 mouse models, 2) the same neurochemicals (NAA, myo -inositol, glutamate) reflect clinical status and pathological progression in SCA1, 3) neurochemical alterations are detectable prior to ataxia onset and overt pathology, and 4) reversal of neurochemical alterations with treatment is detectable by MRS.…”