Limited Effect of Chronic Valproic Acid Treatment in a Mouse Model of Machado-Joseph Disease.
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.
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Sofia
S
Esteves
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Sara
S
Duarte-Silva
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Luana
L
Naia
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Andreia
A
Neves-Carvalho
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Andreia
A
Teixeira-Castro
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Ana Cristina
AC
Rego
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Anabela
A
Silva-Fernandes
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Patrícia
P
Maciel
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D000067699:Ataxin-3 / Q000235:genetics*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D017827:Machado-Joseph Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects / Q000235:genetics; D014635:Valproic Acid / Q000008:administration & dosage*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D014635:Valproic Acid; D000067699:Ataxin-3