title: Reduction in subventricular zone-derived olfactory bulb neurogenesis in a rat model of Huntington's disease is accompanied by striatal invasion of neuroblasts.
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.
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Kandasamy
authors.affiliation: Department of Neurology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosskopf
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klein
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria; Institute of Experimental Neuroregeneration, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Couillard-Despres
authors.affiliation: Department of Ophthalmology, SALK, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Reitsamer
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stephan
authors.affiliation: Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Huu Phuc
authors.initials: HP
authors.lastname: Nguyen
authors.affiliation: Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Department of Neurology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bogdahn
authors.affiliation: Division of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Experimental Therapy, Friedrich-Alexander-University Erlangen-Nurnberg, Erlangen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Aigner
mesh_terms: D000818:Animals; D002465:Cell Movement; D003342:Corpus Striatum / Q000473:pathology*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D020547:Lateral Ventricles / Q000473:pathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology* / Q000502:physiology; D055495:Neurogenesis; D009830:Olfactory Bulb / Q000473:pathology*; D051381:Rats
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins