α-Synuclein Induces Alterations in Adult Neurogenesis in Parkinson Disease Models via p53-mediated Repression of Notch1

Abstract

Background: ␣-Synuclein accumulation alters adult neurogenesis by down-regulation of Notch1. Results: p53 is a negative regulator of Notch1 transcription, and interaction with ␣-synuclein further represses Notch1 expression. Conclusion: p53 mediates the ␣ synuclein-induced alterations of adult neurogenesis. Significance: This might be the first link between p53 effects and aberrant neurogenesis in synucleopathies.

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

“…The expression of many genes implicated in apoptosis, cell cycle progression, neurogenesis and synaptic function were impaired, demonstrating that indeed a-synuclein is involved in many different cell processes that, when deregulated due to differential SNCA expression, may influence neurogenesis. Indeed, rat hippocampal NPCs and mouse ESCs overexpressing SNCA display impaired neuronal differentiation and survival, an effect that is mediated by increased p53-mediated repression of Notch-1 signaling [172,173].…”

Introductory Chapter: Obesity—“OMICS” and Endocrinology

“…Furthermore, p53-associated miRNA dysregulation seems to be of importance, characterizing the aberrant metabolism of adipocyte-derived lipids, linked to the inactivation of nuclearmitochondrial crosstalk. Angiotensin II (AII, from the adipocytokine Apelin) [31] effectuates PPARγ-Sirt1 expression in the adipose tissue [32,84,85], playing a pivotal role in the production and release of adiponectin [31,32]. Furthermore, miRNA species such as miR-34a [86], miR-122, and miR-132 [87,88], which directly obliterate the Sirt1-mediated biochemical processes, bring about adiponectin release, to be construed as a poor activation of hepatic genes governing both glucose and lipid turnover [62].…”

“…The immune-based hypotheses involve the aberrant regulation of Sirt1/p53 and a lack of adaptation to the environment, which implicates an abnormally functioning immune system in both the pathogenesis of insulin resistance and aging [85,86]. Diets, which are high in fat and low in fibrous compounds, are linked to an enhancement of gut microbiota in the circulation, with impact on immune functions, lowered insulin sensitivity, as well as energy homeostasis in both animals and humans [77][78][79][80][81][82][83].…”

“…Hence, diets and our immune system are efficiently "cooperating" with our endogenous intestinal microbial flora (i.e., Gram-negative bacteria) and environmental factors, impinging on dietary fatty acid compositions, which play a pivotal role in the immune homeostasis and reactivity of the liver. The Sirt1's involvement in the mitochondria theory of aging brings about a close link to mitochondrial dysfunction (i.e., Sirt1 downregulation), as well as an abnormal immune response [68,[84][85][86]. An essential requirement of some amino acids (e.g., leucine) [93] may sustain a nuclear and mitochondria p53-associated transport, along with an enhancement in the half-life of p53, as well as a blockage of immune dysfunction and development of NAFLD.…”

Hippocampal Neurogenesis in Neurodegenerative Movement Disorders

“…These data are paralleled by the fact that overexpressed α-syn has been detected in mature, as well as developing neurons and in Sox2-expressing neural stem cells. In this context, impairments of cell cycle-related mechanisms by specifi c α-syn species might play an important role for altered Notch1 signaling in hippocampal neural stem cells in the presence of α-syn in vitro (Desplats et al 2012 ) and in vivo (Crews et al 2008 ).…”