Transforming Growth Factor-Beta Signaling in the Neural Stem Cell Niche: A Therapeutic Target for Huntington's Disease

Hindawi Publishing Corporation Neurology Research International Volume 2011, Article ID 124256, 13 pages doi:10.1155/2011/124256 Review Article Transforming Growth Factor-Beta Signaling in the Neural Stem Cell Niche: A Therapeutic Target for Huntington’s Disease Mahesh Kandasamy,1 Ralf Reilmann,2 Jürgen Winkler,3 Ulrich Bogdahn,4 and Ludwig Aigner1 1 Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria 2 Department of Neurology, University of Münster Medical School, 48129 Münster, Germany 3 Division of Molecular Neurology, University Hospital Erlangen, 91054 Erlangen, Germany 4 Department of Neurology, University of Regensburg, D-93053 Regensburg, Germany Correspondence should be addressed to Ludwig Aigner, Received 15 November 2010; Accepted 19 February 2011 Academic Editor: T. Ben-Hur Copyright © 2011 Mahesh Kandasamy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The neural stem cell niches possess the regenerative capacity to generate new functional neurons in the adult brain, suggesting the possibility of endogenous neuronal replacement after injury or disease. Huntington disease (HD) is a neurodegenerative disease and characterized by neuronal loss in the basal ganglia, leading to motor, cognitive, and psychological disabilities. Apparently, in order to make use of the neural stem cell niche as a therapeutic concept for repair strategies in HD, it is important to understand the cellular and molecular composition of the neural stem cell niche under such neurodegenerative conditions. This paper mainly discusses the current knowledge on the regulation of the hippocampal neural stem cell niche in the adult brain and by which mechanism it might be compromised in the case of HD. 1. Adult Neurogenesis The renowned Spanish neuroanatomist Cajal stated that “Once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In adult centers, the nerve paths are something fixed and immutable: everything may die, nothing may be regenerated” [1]. Therefore, it has been believed that no new neurons are generated in the adult brain and most of the common central nervous system (CNS) pathologies accompanied by neuronal loss cannot be restored. Amongst them are the well-known ones: Parkinson’s disease (PD) accompanied by the degeneration of dopaminergic neurons in the substantia nigra, Alzheimer’s disease (AD) with a neuronal loss in the cerebral cortex and certain subcortical regions, and Huntington’s disease (HD), which is an inherited disease that degenerates neurons in the basal ganglia. According to the above-mentioned dogma, the vast majority of neurons in the mammalian brain are generated during embryonic development [2, 3]. This statement stands true for most of the regions of the adult brain. However, this doctrine ended in 1965 when newly generated neurons were found in two specific regions of the adult brain: the subgranular zone (SGZ) in the dentate gyrus (DG) generates new granular neurons in granule cell layer (GCL) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle wall that gives rise to new cells that migrate along the rostral migratory stream (RMS) to become neurons in the olfactory bulb (OB) [4, 5]. 2. Hippocampal Neurogenesis The hippocampus is a bilateral structure that plays a major role in processing and storage of new information. In the hippocampus, stem cells are located along the border between the granular cell layer (GCL) and the hilus known as subgranular zone (SGZ), where they produce clusterforming precursor cells. From there, neuroblasts migrate into the GCL and become fully matured functional neurons, 2 where they extend dendrites into the molecular layer (ML) and launch mossy fibers to the CA3 region [6, 7]. Following the principle “do or die”, the survival depends on how sufficiently the new cells are integrated into the neural circuit [8–10]. From the neural stem cell to the mature neuron, the cells go through defined steps of division, differentiation, migration, and maturation. Using specific markers, it is possible to investigate the stage-specific changes of SGZ neurogenesis in detail [11, 12]. Further, stem and progenitor cells from adult hippocampus produce neurons that generate action potentials, received functional GABAergic and glutamatergic synaptic inputs [13, 14]. 3. Neurogenesis in the SVZ -RMS-OB System The newborn neurons generated in the OB originate from the subventricular zone (SVZ) of the lateral ventricle (LV). In the adult brain, newly generated SVZ young neurons migrate along the rostral migratory stream (RMS) and proceed to the OB [15]. These neuronal cells integrate upon their arrival into the OB as specific subtypes of interneurons. These subtypes are GABAergic granule cells, which represent the majority of the new OB neurons and a very small number of dopaminergic periglomerular interneurons [16, 17]. The olfactory granule cells are inhibitory interneurons that make their dendritic connections to the mitral cells and to the middle tufted cells. The periglomerular neurons project their dendrites into the corresponding glomerulus and connect to the incoming olfactory axons from the sensory epithelium. It has been shown that these newly formed neurons are functionally integrated into the synaptic circuitry of the OB [16, 18, 19]. 4. The Stem Cell Niches in the Adult Brain The structural and functional maintenance as well as the regenerative potential of most organs depend on a local population of immature cells termed somatic stem cells. In general, stem cells are placed in defined niches or microenvironments, in which they remain quiescent, but where they can be activated to proliferate and to generate a pool of fast dividing, so-called transient amplifying, progenitor cells. They generate lineage-specific precursors, which migrate towards the ultimate destination where they undergo differentiation into an appropriate functionally mature cell type. In the adult brain, new neurons are generated from neural stem and progenitor cells in the hippocampus and in the SVZ-OB system. These neural stem cells (NSCs) have the capacity to proliferate and to self renew giving rise to neurons, astrocytes, and oligodendrocytes. At present, the functional significance of stem cell-derived adult neurogenesis is still under debate, but most studies indicate that adult neurogenesis is involved in learning and memory processes [20–22]. In addition, the presence of NSCs in the adult brain provides the basis for endogenous cell replacement, which could be developed for future therapies in neurodegenerative disease such as HD. Thus, stimulation of endogenous NSC proliferation and functional integration Neurology Research (...truncated)