Abstract
Machado-Joseph disease (MJD) is an inherited neurodegenerative disease, caused by a CAG repeat expansion within the coding region of ATXN3 gene, and which currently lacks effective treatment. In this work we tested the therapeutic efficacy of chronic treatment with valproic acid (VPA) (200mg/kg), a compound with known neuroprotection activity, and previously shown to be effective in cell, fly and nematode models of MJD. We show that chronic VPA treatment in the CMVMJD135 mouse model had limited effects in the motor deficits of these mice, seen mostly at late stages in the motor swimming, beam walk, rotarod and spontaneous locomotor activity tests, and did not modify the ATXN3 inclusion load and astrogliosis in affected brain regions. However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement. In spite of limited results, the use of another dosage of VPA or of VPA in a combined therapy with molecules targeting other pathways, cannot be excluded as potential strategies for MJD therapeutics.
Highlights
Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by an expansion of trinucleotide CAG repeats within the coding region of specific genes [1]
CMVMJD135 mouse model do not present a general hypoacetylation of histones in specific brain regions, we measured the H3 acetylation and we observed a trend towards an increase in H3 acetylation levels upon 5 days of valproic acid (VPA) acute treatment (Fig 1A)
The dosage of VPA of 200mg/kg used in this pre-clinical trial was previously described in a pre-clinical trial Amyotrophic Lateral Sclerosis (ALS), in which neuroprotective and histone acetylation effects were shown [34,35]
Summary
Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by an expansion of trinucleotide CAG repeats within the coding region of specific genes [1] This group of disorders includes spinal bulbar muscular atrophy (SBMA), Huntington’s disease (HD), DentatorubralPallidoluysian atrophy (DRPLA), and six types of spinocerebellar ataxias (SCA’s) [2]. Machado-Joseph disease (MJD) or Spinocerebellar Ataxia type 3 (SCA3) is the most common dominantly inherited SCA worldwide and is caused by the expansion of a polyQ tract in the Cterminus of the ATXN3 gene product [3] Both the normal and expanded ataxin-3 (ATXN3) proteins are expressed ubiquitously, the neurodegeneration in MJD is limited to some brain regions, mainly in cerebellum, brainstem and spinal cord [4]. PLOS ONE | DOI:10.1371/journal.pone.0141610 October 27, 2015
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