Reduction in subventricular zone-derived olfactory bulb neurogenesis in a rat model of Huntington's disease is accompanied by striatal invasion of neuroblasts.

Mahesh Kandasamy,Olaf Riess,Barbara Klein,Katrin Wagner,Ludwig Aigner,Jürgen Winkler,Huu Phuc Nguyen,Sebastien Couillard-Despres,Stephan Von Hörsten,Herbert A Reitsamer,Ulrich Bogdahn,Michael Rosskopf,Michael Stephan

doi:10.1371/journal.pone.0116069

Abstract

Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene (HTT). The primary neuropathology of HD has been attributed to the preferential degeneration of medium spiny neurons (MSN) in the striatum. Reports on striatal neurogenesis have been a subject of debate; nevertheless, it should be considered as an endogenous attempt to repair the brain. The subventricular zone (SVZ) might offer a close-by region to supply the degenerated striatum with new cells. Previously, we have demonstrated that R6/2 mice, a widely used preclinical model representing an early onset HD, showed reduced olfactory bulb (OB) neurogenesis but induced striatal migration of neuroblasts without affecting the proliferation of neural progenitor cell (NPCs) in the SVZ. The present study revisits these findings, using a clinically more relevant transgenic rat model of late onset HD (tgHD rats) carrying the human HTT gene with 51 CAG repeats and mimicking many of the neuropathological features of HD seen in patients. We demonstrate that cell proliferation is reduced in the SVZ and OB of tgHD rats compared to WT rats. In the OB of tgHD rats, although cell survival was reduced, the frequency of neuronal differentiation was not altered in the granule cell layer (GCL) compared to the WT rats. However, an increased frequency of dopamenergic neuronal differentiation was noticed in the glomerular layer (GLOM) of tgHD rats. Besides this, we observed a selective proliferation of neuroblasts in the adjacent striatum of tgHD rats. There was no evidence for neuronal maturation and survival of these striatal neuroblasts. Therefore, the functional role of these invading neuroblasts still needs to be determined, but they might offer an endogenous alternative for stem or neuronal cell transplantation strategies.

Highlights

Huntington’s disease (HD) is an autosomal dominant genetic neurodegenerative disorder of the basal ganglia [1]
We demonstrate that cell proliferation is reduced in the subventricular zone (SVZ) and olfactory bulb (OB) of transgenic rat model of HD (tgHD) rats compared to WT rats
The total number of BrdU-positive cells in the SVZ was significantly reduced in the SVZ of tgHD rats compared to WT rats (WT: 7675.0 ±4972 vs HD: 1697±1139) (Fig. 1 A-C)

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant genetic neurodegenerative disorder of the basal ganglia [1]. HD is caused by the expansion of >39 CAG triplet segments in the exon 1 of the Huntingtin gene (HTT) encoding the Huntingtin protein (Htt) [2,3]. The polyglutamine (PolyQ) repeat length in the HTT gene is proposed to influence age of onset of the disease with symptoms that include movement, cognitive and psychiatric disorders [4,5]. The roles of normal Htt protein as well as the neuropathogenesis induced by the mutant Htt protein are yet to be determined. Further investigations of the neuropathogenesis and endogenous regenerative potential of the HD brain are needed with the ultimate aim to develop innovative strategies to treat this devastating disease

Methods

Results

Conclusion