Novel Approaches Used to Examine and Control Neurogenesis in Parkinson0s Disease

International Journal of Molecular Sciences Review Novel Approaches Used to Examine and Control Neurogenesis in Parkinson0s Disease Alla B. Salmina 1,2,*, Marina R. Kapkaeva 1, Anna S. Vetchinova 1 and Sergey N. Illarioshkin 1 1 Research Center of Neurology, 125367 Moscow, Russia; [email protected] (M.R.K.); [email protected] (A.S.V.); [email protected] (S.N.I.) 2 Research Institute of Molecular Medicine & Pathobiochemistry, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia * Correspondence: [email protected] Abstract: Neurogenesis is a key mechanism of brain development and plasticity, which is impaired in chronic neurodegeneration, including Parkinson’s disease. The accumulation of aberrant α-synuclein is one of the features of PD. Being secreted, this protein produces a prominent neurotoxic effect, alters synaptic plasticity, deregulates intercellular communication, and supports the development of neuroinflammation, thereby providing propagation of pathological events leading to the establish- ment of a PD-specific phenotype. Multidirectional and ambiguous effects of α-synuclein on adult neurogenesis suggest that impaired neurogenesis should be considered as a target for the prevention of cell loss and restoration of neurological functions. Thus, stimulation of endogenous neurogenesis or cell-replacement therapy with stem cell-derived differentiated neurons raises new hopes for the development of effective and safe technologies for treating PD neurodegeneration. Given the rapid development of optogenetics, it is not surprising that this method has already been repeatedly tested in manipulating neurogenesis in vivo and in vitro via targeting stem or progenitor cells. However, Citation: Salmina, A.B.; Kapkaeva, niche astrocytes could also serve as promising candidates for controlling neuronal differentiation and M.R.; Vetchinova, A.S.; Illarioshkin, S.N. Novel Approaches Used to improving the functional integration of newly formed neurons within the brain tissue. In this review, Examine and Control Neurogenesis we mainly focus on current approaches to assess neurogenesis and prospects in the application of in Parkinson0s Disease. Int. J. Mol. Sci. optogenetic protocols to restore the neurogenesis in Parkinson’s disease. 2021, 22, 9608. https://doi.org/ 0 10.3390/ijms22179608 Keywords: Parkinson s disease; α-synuclein; neurogenesis; neural stem cell; neural progenitor cell; astrocyte; optogenetics Academic Editors: Piotr D. Bregestovski and Carlo Matera Received: 29 July 2021 1. Introduction: Neurogenesis in the Healthy and Parkinson’s Disease-Affected Brains Accepted: 2 September 2021 1.1. Key Characteristics of Adult Neurogenesis Published: 4 September 2021 Neurogenesis is a mechanism of brain development and plasticity. Embryonic neuro- Publisher’s Note: MDPI stays neutral genesis provides new neurons for brain growth, whereas adult neurogenesis is required with regard to jurisdictional claims in for memory consolidation and tissue repair, mood regulation, and social recognition [1–4]. published maps and institutional affil- Functional competence of adult-born neurons results in their successful integration into iations. pre-existing neural circuits, for instance, in the hippocampus, which is associated with activity-mediated acceleration of dendritic spines formation [5]. Therefore, the efficacy of neurogenesis in the embryonic brain corresponds to appropriate brain development and maturation. Adult neurogenesis could be considered as efficient if brain plasticity meets the current needs in cognition, social interactions, expression of emotions, memory Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. consolidation and retrieval, forgetting, and experience-driven circuits remodeling. This article is an open access article The key pool of cells that could be activated to provide new neurons and astrocytes is distributed under the terms and represented by neural stem cells (NSCs) that are found in highly specialized neurogenic conditions of the Creative Commons niches (subventricular zone, SVZ, and subgranular zone of the hippocampus, SGZ), as Attribution (CC BY) license (https:// well in some other brain regions (cerebellum, substantia nigra, cortex), and in loci with the creativecommons.org/licenses/by/ facilitated access to regulatory molecules, i.e., in the periventricular area with ischemia- or 4.0/). neuroinflammation-mediated compromised blood-brain barrier (BBB) [6,7]. NSCs exhibit Int. J. Mol. Sci. 2021, 22, 9608. https://doi.org/10.3390/ijms22179608 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 30 genic niches (subventricular zone, SVZ, and subgranular zone of the hippocampus, SGZ), as well in some other brain regions (cerebellum, substantia nigra, cortex), and in loci with Int. J. Mol. Sci. 2021, 22, 9608 the facilitated access to regulatory molecules, i.e., in the periventricular area with ische-2 of 29 mia- or neuroinflammation-mediated compromised blood-brain barrier (BBB) [6,7]. NSCs exhibit two pivotal characteristics: (1) the ability to self-renew and to produce copies of themselves by symmetric or asymmetric division; (2) multipotency to produce neuraltwo pivotal progenitor characteristics: cells (NPCs) (1) thethat ability are able to self-renew to differentiate and to into produce neurons, copies astrocytes, of themselves or oligodendrogliaby symmetric or [8–10]. asymmetric The proliferation division; (2) of multipotency NSCs is under to produce the tight neural control progenitor of the local cells microenvironment(NPCs) that are able consisting to differentiate of numerous into neurons, soluble astrocytes, molecules: or neurotransmitters oligodendroglia [8 (GABA,–10]. The glutamate,proliferation dopamine, of NSCs etc.), is under neuropeptides the tight control (oxytocin, of the angiotensin, local microenvironment etc.), cytokines consisting (interleukins,of numerous chemokines, soluble etc.), molecules: metabolites neurotransmitters (lactate, NAD+), (GABA, extracellular glutamate, matrix dopamine, proteins, and etc.), accessoryneuropeptides cells (oxytocin,(astrocytes, angiotensin, brain microve etc.),ssel cytokines endothelial (interleukins, cells) aimed chemokines, to prevent etc.), + non-reasonablemetabolites (lactate, utilization NAD of), the extracellular NSCs pool, matrix to coordinate proteins, cell and fate, accessory and to cellsdrive (astrocytes, cell proliferation,brain microvessel differentiation, endothelial and cells)migration aimed on to demand prevent non-reasonable(Figure 1). In addition utilization to of the the NSCs pool, to coordinate cell fate, and to drive cell proliferation, differentiation, and above-mentioned factors, local hypoxia in the neurogenic niche serves as a signal to migration on demand (Figure1). In addition to the above-mentioned factors, local hypoxia control the NSC’s recruitment [11]. in the neurogenic niche serves as a signal to control the NSC’s recruitment [11]. Figure 1. A simplified scheme of intercellular communications within the neurogenic niche. The local Figure 1. A simplified scheme of intercellular communications within the neurogenic niche. The microenvironment is established due to the activity of neuronal, astroglial, and endothelial cells that local microenvironment is established due to the activity of neuronal, astroglial, and endothelial cellsare ablethat toare release able to various release molecules various molecules (growth factors, (growth neurotransmitters, factors, neurotransmitters, cytokines, gliotransmitters,cytokines, gliotransmitters,metabolites) affectingmetabolites) cell fateaffecting within cell the fate niche. within Abbreviations the niche. used:Abbreviations NSC—neural used stem: NSC—neural cell, NPC— stemneural cell, progenitor NPC—neural cell, NB—neuroblast, progenitor cell, IN—immature NB—neuroblast, neuron, IN—immature N—neuron, A—astrocyte,neuron, N—neuron, BMEC— A—astrocyte,brain microvessel BMEC—brain endothelial microvessel cell, E/I—excitation-inhibition endothelial cell, E/I—excitation-inhibition balance. balance. PostnatalPostnatal ontogenesis, ontogenesis, neurodegeneration, neurodegeneration, and agingaging areare associated associated with with progressive progres- siveloss loss of NSCs of NSCs (radial (radial glia glia cells, cells, RGCs) RGCs) in the in rodentthe rodent hippocampus hippocampus [10], thereby[10], thereby suggesting sug- gestingthat mechanisms that mechanisms preventing preventing the depletion the depletio of then of NSCs the NSCs pool camepool came to be lessto be efficient less effi- in cientolder in brains. older Indeed, brains. in Indeed, human SVZ,in human the density SVZ, of the RGCs density reduces of from RGCs mid-gestation reduces from until mid-gestationthe perinatal period,until the and perinatal in the human period, SGZ, and the in decline the human of RGCs SGZ, number the decline is observed of RGCs from numberearly ages is observed of development from early until ages 5 years of development old and then until in adulthood 5 years old [12 and]. then in adulthood [12].The predominant view on neurogenic events in the adult brain states that enhanced neurogenesisThe predominant is required view for on (re)cognition neurogenic events and memory, in the adult whereas brain reduced states that neurogenesis enhanced neurogenesismanifests aberrant is required brain for plasticity (re)cognitio [13].n However,and memory, recent whereas data suggest reduced that neurogenesis the general

Load more