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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    • "Rapamycin has been shown to reduce aggregation of expanded polyQ in transfected cells (Ravikumar et al., 2002), to protect against neurodegeneration in a fly model of Huntington disease (HD), and to improve motor performance and decrease aggregate formation in a mouse model of HD (Ravikumar et al., 2004). Lithium chloride (LiCl), an mTOR-independent autophagy inducer has been shown to improve motor performance and depressive-like behavior in a mouse model of HD, as well as to improve neuropathology and motor function in a SCA1 mouse model (Wood and Morton, 2003; Watase et al., 2007). We have recently shown that 19 weeks of LiCl (10.4 mg/kg) treatment in the CMVMJD135 mouse model, had limited effects on the motor phenotype of these animals, despite its ability to induce autophagy both in the chronic and acute treatment (Duarte-Silva et al., 2014). "
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    ABSTRACT: A major pathological hallmark in several neurodegenerative disorders, like polyglutamine disorders (polyQ), including Machado-Joseph disease (MJD), is the formation of protein aggregates. MJD is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormal protein, which is prone to misfolding and forms cytoplasmic and nuclear aggregates within neurons, ultimately inducing neurodegeneration. Treatment of proteinopathies with drugs that up-regulate autophagy has shown promising results in models of polyQ diseases. Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (m-TOR), while lithium chloride (LiCl) acts by inhibiting inositol monophosphatase, both being able to induce autophagy. We have previously shown that chronic treatment with LiCl (10.4 mg/Kg) had limited effects in a transgenic MJD mouse model. Also, others have shown that CCI-779 had mild positive effects in a different mouse model of the disease. It has been suggested that the combination of mTOR-dependent and -independent autophagy inducers could be a more effective therapeutic approach. To further explore this avenue towards therapy, we treated CMVMJD135 transgenic mice with a conjugation of CCI-779 and LiCl, both at concentrations known to induce autophagy and not to be toxic. Surprisingly, this combined treatment proved to be deleterious to both wild-type and transgenic animals, failing to rescue their neurological symptoms and actually exerting neurotoxic effects. These results highlight the possible dangers of manipulating autophagy in the nervous system and suggest that a better understanding of the potential disruption in the autophagy pathway in MJD are required before successful long-term autophagy modulating therapies can be developed.
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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.
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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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