Lithium Therapy Improves Neurological Function and Hippocampal Dendritic Arborization in a Spinocerebellar Ataxia Type 1 Mouse Model

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
PLoS Medicine (Impact Factor: 14.43). 06/2007; 4(5):e182. DOI: 10.1371/journal.pmed.0040182
Source: PubMed


Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1(154Q/2Q) mice) that replicates many features of the human disease.
Sca1(154Q/2Q) mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1(154Q/2Q) mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity.
The effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.

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    • "The 50% and maximum survival durations were elongated from 217 days (Atxn1-KI) to 282 days (Atxn1-KI;HMGB1) and from 274 days (Atxn1-KI) to 360 days (Atxn1-KI;HMGB1), respectively. This elongation rate is one of the best results reported with Atxn1- KI mice (Watase et al, 2007). In our analysis, the thickness of the molecular layer was decreased at the onset of symptoms (9 weeks). "
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    ABSTRACT: Mutant ataxin-1 (Atxn1), which causes spinocerebellar ataxia type 1 (SCA1), binds to and impairs the function of high-mobility group box 1 (HMGB1), a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. In this study, we established that transgenic or virus vector-mediated complementation with HMGB1 ameliorates motor dysfunction and prolongs lifespan in mutant Atxn1 knock-in (Atxn1-KI) mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB1 function, such as nuclear DNA damage repair and nuclear transcription. The dysfunction and the improvement of mitochondrial DNA damage repair functions are tightly associated with the exacerbation and rescue, respectively, of symptoms, supporting the involvement of mitochondrial DNA quality control by HMGB1 in SCA1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB1 could be downstream effects. Although extracellular HMGB1 triggers inflammation mediated by Toll-like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB1 does not induce such side effects. Thus, viral delivery of HMGB1 is a candidate approach by which to modify the disease progression of SCA1 even after the onset.
    EMBO Molecular Medicine 12/2014; 7(1). DOI:10.15252/emmm.201404392 · 8.67 Impact Factor
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    • "The dysregulation of several neuronal genes that has been observed in the tissue of humans with SCA1 has also been found in the Purkinje cells of SCA1 transgenic mice, even at the pre-symptomatic stage [4]. In light of this notion, Watase et al. [5] treated Sca1154Q/+ mice with lithium—which exerts neuroprotective effects possibly by affecting gene transcription—and demonstrated that lithium rescues several SCA1 phenotypes in this model. "
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    ABSTRACT: We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1(154Q/+) ). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+) mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1(154Q/+) mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1(154Q/+) cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1(154Q/+) mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002), with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1(154Q/+) mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1(154Q/+) mice and restored upon lithium treatment, might relate to lithium neuroprotective properties.
    PLoS ONE 08/2013; 8(8):e70610. DOI:10.1371/journal.pone.0070610 · 3.23 Impact Factor
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    • "Considering that our data demonstrates D2Rs co-localized with S100B in PC vacuoles (Fig. 6A), the continuous expression of mutant ataxin-1 to form vacuoles may be depleting functional D2Rs from the PC soma, dysregulating cAMP production and increasing PKA activity. Further evidence implicating D2Rs in the SCA1 pathogenesis comes from the beneficial effects of lithium therapy to SCA1 Tg mice (Watase et al. 2007). The stimulatory effects of lithium on the transcription of the D2R gene was shown in rats fed chow containing 0.2% LiCO 3 , which resulted in an increased D2R mRNA expression level and an increased transcription rate of the D2R gene in the rat brain striatum (Kameda et al. 2001). "
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    ABSTRACT: J. Neurochem. (2010) 114, 706–716. Spinocerebellar ataxia 1 (SCA1) is a dominantly inherited neurodegenerative disease associated with progressive ataxia resulting from the loss of cerebellar Purkinje cells (PCs) and neurons in the brainstem. In PCs of SCA1 transgenic mice, the disease causing ataxin-1 protein mediates the formation of S100B containing cytoplasmic vacuoles and further self-aggregates to form intranuclear inclusions. The exact function of the ataxin-1 protein is not fully understood. However, the aggregation and neurotoxicity of the mutant ataxin-1 protein is dependent on the phosphorylation at serine 776 (S776). Although protein kinase A (PKA) has been implicated as the S776 kinase, the mechanism of PKA/ataxin-1 regulation in SCA1 is still not clear. We propose that a dopamine D2 receptor (D2R)/S100B pathway may be involved in modulating PKA activity in PCs. Using a D2R/S100B HEK stable cell line transiently transfected with GFP-ataxin-1[82Q], we demonstrate that stimulation of the D2R/S100B pathway caused a reduction in mutant ataxin-1 S776 phosphorylation and ataxin-1 aggregation. Activation of PKA by forskolin resulted in an enhanced S776 phosphorylation and increased ataxin-1 nuclear aggregation, which was suppressed by treatment with D2R agonist bromocriptine and PKA inhibitor H89. Furthermore, treating SCA1 transgenic PC slice cultures with forskolin induced neurodegenerative morphological abnormalities in PC dendrites consistent with those observed in vivo. Taken together our data support a mechanism where PKA dependent mutant ataxin-1 phosphorylation and aggregation can be regulated by D2R/S100B signaling.
    Journal of Neurochemistry 08/2010; 114(3):706-16. DOI:10.1111/j.1471-4159.2010.06791.x · 4.28 Impact Factor
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