Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1

Abstract

SCA1 is an adult-onset, dominantly inherited neurodegenerative disease caused by expansion of a glutamine repeat tract in ATXN1. Although the precise function of ATXN1 remains elusive, it appears to play a role in transcriptional repression. We find that mutant ATXN1 suppresses transcription of the neurotrophic and angiogenic factor VEGF. We also show that genetic or pharmacologic replenishment of VEGF mitigates SCA1 pathogenesis, suggesting a novel therapeutic strategy for this incurable disease.

Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

“…Previous studies have observed that, by the end of the first postnatal month, SCA1 mice have synaptic abnormalities that involve alterations in climbing fiber (CF) glutamatergic input onto PCs (8,9,13). In this report, we demonstrate that the cerebellar network is altered in SCA1 even earlier than this through the involvement of cerebellar stem cells.…”

“…Mice were perfused with EM grade 4% PFA. Cerebellar samples were isolated and embedded in OCT compound (13), and 150 μm-thick sagittal sections were cut using a vibratome (Leica). The sections were post-fixed in 2% PFA and 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer (pH 7.3) and incubated with unbuffered 2% osmium tetroxide.…”

“…In both knockin and transgenic models of SCA1, defects in Purkinje cell (PC) synaptic connectivity precede ataxia (6)(7)(8), and gene expression changes appear within the first few weeks of life (8)(9)(10)(11)(12)(13). During this early period, neurogenesis is still taking place within a niche of postnatal stem cells in the cerebellar white matter, which led us to ask whether early neurodevelopment might go awry in ways that alter the neural circuitry of the cerebellum.…”

Histone Deacetylase 3 Is Necessary for Proper Brain Development

“…Because changes in the number of DAPI-stained cells could contribute to the changes in the number of positive cells, positive cells counts were normalized to DAPI and expressed as a percentage of wild-type littermate controls. Calbindin staining intensity in the Nes-Cre/HDAC3 cKO and wild-type littermates was assessed using NIH ImageJ Software as described previously (18). For measurement of cortex or staining widths, NIS-elements Advanced Research software was used to calibrate the images, and then the measurement tools were used to quantify widths.…”

Targeted deletion of Vegfa in adult mice induces vision loss

“…Degeneration of photoreceptors, RPE cells, and the choriocapillaris is associated with age-related macular degeneration (AMD), the leading cause of vision loss in industrialized nations. While VEGF clearly plays a role in physiological vascular development (1-4) and pathological neovascularization (5,6) in the retina and the choroid, there is increasing evidence that it is also important for the trophic maintenance of neurons (7)(8)(9). Inhibition of VEGF has become the mainstay of therapy for treating AMD (10)(11)(12), and increasingly potent VEGF antagonists have recently been introduced into the clinics.…”