Transcriptional Activation of Low-Density Lipoprotein Receptor Gene by DJ-1 and Effect of DJ-1 on Cholesterol Homeostasis

DJ-1 is a novel oncogene and also causative gene for familial Parkinson’s disease park7. DJ-1 has multiple functions that include transcriptional regulation, anti-oxidative reaction and chaperone and mitochondrial regulation. For transcriptional regulation, DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found the low-density lipoprotein receptor (LDLR) gene is a transcriptional target gene for DJ-1. Reduced expression of LDLR mRNA and protein was observed in DJ-1-knockdown cells and DJ-1-knockout mice and this occurred at the transcription level. Reporter gene assays using various deletion and point mutations of the LDLR promoter showed that DJ-1 stimulated promoter activity by binding to the sterol regulatory element (SRE) with sterol regulatory element binding protein (SREBP) and that stimulating activity of DJ-1 toward LDLR promoter activity was enhanced by oxidation of DJ-1. Chromatin immunoprecipitation, gel-mobility shift and co-immunoprecipitation assays showed that DJ-1 made a complex with SREBP on the SRE. Furthermore, it was found that serum LDL cholesterol level was increased in DJ-1-knockout male, but not female, mice and that the increased serum LDL cholesterol level in DJ-1-knockout male mice was cancelled by administration with estrogen, suggesting that estrogen compensates the increased level of serum LDL cholesterol in DJ-1-knockout female mice. This is the first report that DJ-1 participates in metabolism of fatty acid synthesis through transcriptional regulation of the LDLR gene

Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer’s disease (AD) and represents a large health burden to society. Genetic and oxidative risk factors have been proposed as possible causes, but their relative contribution remains unclear. Dysfunction of alpha-synuclein (α-syn) has been associated with PD due to its increased presence, together with iron, in Lewy bodies. Brain oxidative damage caused by iron may be partly mediated by α-syn oligomerization during PD pathology. Also, α-syn gene dosage can cause familial PD and inhibition of its gene expression by blocking translation via a newly identified Iron Responsive Element-like RNA sequence in its 5’-untranslated region may provide a new PD drug target

Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition.

There is a continued unmet need for treatments that can slow Parkinson's disease progression due to the lack of understanding behind the molecular mechanisms underlying neurodegeneration. Since its discovery, ferroptosis has been implicated in several diseases and represents a therapeutic target in Parkinson's disease. Here, we use two highly relevant human dopaminergic neuronal models to show that endogenous levels of α-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis. We show that reducing α-synuclein expression in dopaminergic neurons leads to ferroptosis evasion, while elevated α-synuclein expression in patients' small-molecule-derived neuronal precursor cells with SNCA triplication causes an increased vulnerability to lipid peroxidation and ferroptosis. Lipid profiling reveals that ferroptosis resistance is due to a reduction in ether-linked phospholipids, required for ferroptosis, in neurons depleted of α-synuclein (α-syn). These results provide a molecular mechanism linking α-syn levels to the sensitivity of dopaminergic neurons to ferroptosis, suggesting potential therapeutic relevance

Vascular dysfunction in a mouse model of Rett Syndrome and effects of Curcumin treatment

Mutations in the coding sequence of the X-linked gene MeCP2 (Methyl CpG–binding protein), are present in around 80% of patients with Rett Syndrome, a common cause of mental retardation in female and to date without any effective pharmacological treatment. A relevant, and so far unexplored feature of RTT patients is a marked reduction in peripheral circulation. To investigate the relationship between loss of MeCP2 and this clinical aspect, we used a MeCP2 null mouse model, male (MeCP2y/-) and female (MeCP2+/-), for functional, pharmacological and behavioural studies. The functional studies performed on dissected branches of mesenteric arterial tree mounted on glass microcannule in a pressurized myograph, demonstrated a dramatic endothelial-dependent vascular reactivity impairment in MeCP2+/- compared to control littermate. The mesenteric arteriole preincubation with NOS inhibitors or ascorbic acid indicate a decrease Nitric Oxide (NO) availability and the increased presence of Reactive Oxygen Species (ROS). Consistently, the RTT mouse model exhibited a decreased expression in both mRNA and peptide eNOS in the arterioles and a higher systemic oxidative level. MeCP2 knockout mice show stereotyped movements and less resting time when compared to control littermates. Chronic curcumin treatment of female MeCP2+/- mice was able to reverse this vascular phenotype and ameliorate the mouse RTT behavioural symptomatology by decreasing stereotyped movements and by increasing resting time. These data indicate that in the absence of MeCP2 peripheral circulation is impaired by an altered vascular reactivity and decreased arteriolar eNOS expression and NO production. Further, they provide a physiological/molecular rational for the use of curcumin as a treatment to improve the health of RTT patients

Ergodic universality of some topological dynamical systems

The Krieger generator theorem says that every invertible ergodic measure-preserving system with finite measure-theoretic entropy can be embedded into a full shift with strictly greater topological entropy. We extend Krieger's theorem to include toral automorphisms and, more generally, any topological dynamical system on a compact metric space that satisfies almost weak specification, asymptotic entropy expansiveness, and the small boundary property. As a corollary, one obtains a complete solution to a natural generalization of an open problem in Halmos's 1956 book regarding an isomorphism invariant that he proposed

The Nrf2 transcriptional target, OSGIN1, contributes to the cytoprotective properties of dimethyl fumarate

Understanding how defense signaling pathways regulate neuronal protection in the compromised central nervous system (CNS) is essential for combating neurodegenerative disorders. This is apparent in the intrinsic activation of the transcription factor Nrf2 during periods of oxidative stress, a hallmark of neurodegeneration. This regulator of the antioxidant response induces the transcription of genes essential for protecting against oxidative stress-induced damage and is a prime target for drug discovery. Delayed-release dimethyl fumarate (DMF), currently approved for the treatment of relapsing-remitting forms of multiple sclerosis (MS), is believed to mediate its effect via the Nrf2 pathway; however, the exact mechanisms of action are unknown. The primary aim of the studies outlined in this dissertation was to identify the molecular mechanisms of Nrf2 regulation and subsequent cellular protection conferred by DMF and its bioactive metabolite, monomethyl fumarate (MMF). For this thesis study, transcriptional profiling studies following oral administration of DMF were conducted to characterize DMF pharmacodynamic responses in the central nervous system (CNS) and peripheral tissues to understand the functional effects of DMF in vivo as well as explore the necessity of Nrf2 in this process. Data from these studies confirm earlier findings that DMF activates transcription of Nrf2 target genes in the CNS and periphery; however, tissue-specific gene expression was also observed, indicating additional levels of transcriptional control beyond Nrf2 activation. These findings suggest that there may be unique cytoprotective and immunomodulatory capabilities of DMF within specific tissues. In the CNS, a novel Nrf2 transcriptional target gene OSGIN1 was identified to be significantly upregulated following DMF treatment in vivo; however, the contribution of this gene to the pharmacodynamic properties of DMF or MMF has not been previously described. Therefore, the in vitro effects of MMF on OSGIN1 expression were characterized, and the necessity of OSGIN1 in mediating cytoprotective effects against toxic oxidative stress in human astrocytes was evaluated. These data identify a potential mechanism for MMF-mediated cytoprotection in human astrocytes that function in an OSGIN1 and p53-dependent manner. Overall, the experiments described in this dissertation allow for a broader understanding of endogenous cellular protection and how it can be used to combat CNS disorders