Abstract
Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin-1 (ATXN1) gene and characterized by motor deficits and cerebellar neurodegeneration. Even though mutant ATXN1 is expressed from an early age, disease onset usually occurs in patient’s mid-thirties, indicating the presence of compensatory factors that limit the toxic effects of mutant ATXN1 early in disease. Brain derived neurotrophic factor (BDNF) is a growth factor known to be important for the survival and function of cerebellar neurons. Using gene expression analysis, we observed altered BDNF expression in the cerebella of Purkinje neuron specific transgenic mouse model of SCA1, ATXN1[82Q] mice, with increased expression during the early stage and decreased expression in the late stage of disease. We therefore investigated the potentially protective role of BDNF in early stage SCA1 through intraventricular delivery of BDNF via ALZET osmotic pumps. Extrinsic BDNF delivery delayed onset of motor deficits and Purkinje neuron pathology in ATXN1[82Q] mice supporting its use as a novel therapeutic for SCA1.
Highlights
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited and fatal neurodegenerative disease resulting from an overexpansion of CAG repeats within the Ataxin-1 (ATXN1) gene (Banfi et al, 1996; Zoghbi and Orr, 2009)
We have found that expression of neuroprotective factor Brain derived neurotrophic factor (BDNF) is increased early and decreased late in ATXN1[82Q] mice (Cvetanovic et al, 2015; Supplementary Table S1), 5-weekold ATXN1[82Q] mice 6.87 vs. 5.3 fragments per kilobase of exon per million reads mapped (FPKM) in wild-type (WT) littermates, p = 0.00005, adjusted q = 0.0165; 12-week-old ATXN1[82Q] mice 3.2 vs. 5.03 fragments per kilobase of exon per million reads mapped (FPKM) in WT littermates, p = 0.00015, adjusted q = 0.0021)
We demonstrated that reducing astrogliosis early in SCA1, through inducible genetic inhibition of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling selectively in astroglia, exacerbates motor deficits and neuropathology in ATXN1[82Q] mice (Kim et al, 2018)
Summary
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited and fatal neurodegenerative disease resulting from an overexpansion of CAG repeats within the Ataxin-1 (ATXN1) gene (Banfi et al, 1996; Zoghbi and Orr, 2009). SCA1 belongs to a group of polyglutamine (polyQ) disorders that includes SCA2, 3, 6, 7, 17, spinobulbar muscular atrophy, Huntington’s disease (HD), and dentatorubropallidoluysian atrophy (Genis et al, 1995; Gusella and MacDonald, 2000; La Spada and Taylor, 2010). Clinical onset of SCA1 is characterized by ataxia, or loss of motor coordination and balance, which typically presents during patient’s mid-thirties (Genis et al, 1995; Orr and Zoghbi, 2007; Rüb et al, 2013; Matilla-Dueñas et al, 2014). Progressive degradation of motor function leads to death within 10–20 years following clinical onset (Rüb et al, 2013). No treatments exist for SCA1 (Paulson et al, 2017).
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