Neurogenesis in Substantia Nigra of Parkinsonian Brains?

Experimental Neurology, Philipps University, D-35033 Marburg, Germany.
Journal of Neural Transmission (Impact Factor: 2.4). 01/2009; DOI: 10.1007/978-3-211-92660-4_23
Source: PubMed


The clinical motor dysfunction in Parkinson's disease is primarily the consequence of a progressive degeneration of dopaminergic neurons in the substantia nigra of the nigrostriatal pathway. The degeneration of this tract provokes a depletion of dopamine in the striatum, where it is required as a permissive factor for normal motor function. Despite intense investigations, no effective therapy is available to prevent the onset or to halt the progression of the neuronal cell loss. Therefore, recent years have seen research into the mechanisms of endogenous repair processes occurring in the adult brain, particularly in the substantia nigra. Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, the remainder of the brain is considered to be primarily nonneurogenic in nature, implying that no new neurons are produced there under normal conditions. The occurrence of adult neurogenesis in the substantia nigra under the pathological conditions of Parkinson's disease, however, remains controversial. Here, we review the published evidence of whether adult neurogenesis exists or not within the substantia nigra, where dopaminergic neurons are lost in Parkinson's disease.

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Available from: Oscar Arias-Carrion,
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    • "Reorganization of cell migratory tracks would address the conundrum that endogenous neurogenesis is restricted to discrete brain areas, like the SVZ and SGZ, that are distinct from the brain areas where cells are lost in AD, PD, and HD. It is possible that future strategies targeting endogenous neurogenesis will facilitate migration of cells, for example, from the SVZ into the striatum to replace the medium spiny neurons lost in HD or supply DA in place of the DA terminals lost in PD (Cho et al. 2007; Arias-Carrion et al. 2009), or from the DG into the CA1 and cortex in AD. Indeed it has been shown that transplantation of exogenous NSPC in a rat model of PD triggers the expression of various trophic factors such as SDF-1α in endogenous NSPCs, leading to enhanced migration of endogenous NSPC to the graft site (Madhavan et al. 2009). "
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    ABSTRACT: With the growth of the aging population and increasing life expectancy, the diagnosis of age-related neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer's, Huntington's, and Parkinson's diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. To this end, the self-renewing and multipotent properties of neural stem/precursor cells (NSPCs) that exist in the adult brain suggest that NSPCs could contribute to a therapy for replacement of damaged or lost neurons. Although a wealth of research demonstrates the proof-of-concept that NSPC transplantation has therapeutic potential, there are considerable barriers between the theory of cell transplantation and clinical implementation. However, a new view on harnessing the power of NSPC for treatment of neurodegenerative disorders has emerged, and focuses on treating neuropathological aspects of the disease prior to the appearance of overt neuronal loss. For example, rather than merely replacing lost neurons, NSPCs are now being considered for their ability to provide trophic support. Here we review the evolution of how the field has considered application of NSPCs for treatment of neurodegeneration disorders. We discuss the challenges posed by the "traditional" view of neurodegeneration - overt cell loss - for utilization of NSPCs for treatment of these disorders. We also review the emergence of an alternative strategy that involves fine-tuning the neurogenic capacity of existing adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. We conclude with our opinion that for this strategy to become a translational reality, it requires a thorough understanding of NSPCs, the dynamic process of adult neurogenesis, and a better understanding of the pathological trajectory of each neurodegenerative disease.
    03/2015; 1(3):335-351.
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    • "Regarding PD, stem cells and related cellular plasticity markers are also altered in relevant animal models [24–26], but only few studies exist on proliferative changes in human PD brain [26], most of which have focused on the SN [27, 28] and subventricular zone (SVZ) [29, 30]. In the human SN and SVZ, discrepant results have been obtained between different studies, and this topic remains subject of debate [26, 29, 31–34]. "
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    ABSTRACT: Besides dopamine-deficiency related motor symptoms, nonmotor symptoms, including cognitive changes occur in Parkinson's disease (PD) patients, that may relate to accumulation of íµí»¼-synuclein in the hippocampus (HC). This brain region also contains stem cells that can proliferate. This is a well-regulated process that can, for example, be altered by neurodegenerative conditions. In contrast to proliferation in the substantia nigra and subventricular zone, little is known about the HC in PD. In addition, glial cells contribute to neurodegenerative processes and may proliferate in response to PD pathology. In the present study, we questioned whether microglial cells proliferate in the HC of established PD patients versus control subjects or incidental Lewy body disease (iLBD) cases as a prodromal state of PD. To this end, proliferation was assessed using the immunocytochemical marker minichromosome maintenance protein 2 (MCM2). Colocalization with Iba1 was performed to determine microglial proliferation. MCM2-positive cells were present in the HC of controls and were significantly increased in the presymptomatic iLBD cases, but not in established PD patients. Microglia represented the majority of the proliferating cells in the HC. This suggests an early microglial response to developing PD pathology in the HC and further indicates that neuroinflammatory processes play an important role in the development of PD pathology.
    Neural Plasticity 08/2014; 2014. DOI:10.1155/2014/959154 · 3.58 Impact Factor
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    • "Accumulated evidence suggests that there are multiple neurogenic niches in the brain apart from the hippocampal dentate gyrus sub granular zone (SGZ) and the cerebral sub ventricular zone (SVZ). These include the hypothalamus (Lee et al., 2012), cerebellum (Keller et al., 2004; Ponti et al., 2005, 2006, 2008, 2010; Bonfanti and Ponti, 2008; Hajihosseini et al., 2008), striatum (Tattersfield et al., 2004; Ninomiya et al., 2006; Luzzati et al., 2007; Snyder et al., 2010; Danilov et al., 2012; Delavaran et al., 2013; Ernst et al., 2014; Kempermann, 2014), and SN (Bayer et al., 1995; Zhao et al., 2003; Chen et al., 2005; Van Kampen and Robertson, 2005; Yoshimi et al., 2005; Arias-Carrión et al., 2006, 2009; Freundlieb et al., 2006; Shan et al., 2006; Steiner et al., 2006; Esposito et al., 2007; Mandel et al., 2007; Di Giovanni et al., 2009; Ries et al., 2009; Park et al., 2012; Sun et al., 2012a,b; Worlitzer et al., 2013). Therefore, APα may promote the generation of new cells locally in SN. "
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    ABSTRACT: Reinstalling the neurobiological circuits to effectively change the debilitating course of neurodegenerative diseases is of utmost importance. This reinstallation requires generation of new cells which are able to differentiate into specific types of neurons and modification of the local environment suitable for integration of these new neurons into the neuronal circuits. Allopregnanolone (APα) seems to be involved in both of these processes, and therefore, is a potential neurotrophic agent. Loss of dopamine neurons in the substantia nigra (SN) is one of the main pathological features of Parkinson's and also in, at least, a subset of Alzheimer's patients. Therefore, reinstallation of the dopamine neurons in nigrostriatal tract is of unique importance for these neurodegenerative diseases. However, for the neurogenic status and the roles of allopregnanolone in the nigrostriatal tract, the evidence is accumulating and debating. This review summarizes recent studies regarding the neurogenic status in the nigrostriatal tract. Furthermore, special attention is placed on evidence suggesting that reductions in allopregnenalone levels are one of the major pathological features in PD and AD. This evidence has also been confirmed in brains of mice that were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or those bearing neurodegenerative mutations. Lastly, we highlight studies showing that allopregnanalone can augment the number of total cells and dopaminergic neurons via peripheral exogenous administration.
    Frontiers in Cellular Neuroscience 08/2014; 8:224. DOI:10.3389/fncel.2014.00224 · 4.29 Impact Factor
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