Roya Saffary

Bio: Roya Saffary is an academic researcher from Stanford University. The author has contributed to research in topics: Ubiquitin ligase & Neurodegeneration. The author has an hindex of 5, co-authored 8 publications receiving 472 citations. Previous affiliations of Roya Saffary include University of Maryland, Baltimore & Johns Hopkins University.

Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death.

Abstract: Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson9s disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-α treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.

FMRP Regulates the Transition from Radial Glial Cells to Intermediate Progenitor Cells during Neocortical Development

Abstract: During vertebrate cortical neurogenesis, radial glial cells (RGCs) serve as neural stem cells that generate neurons directly or indirectly through intermediate progenitor cells (IPCs). The transition from RGCs to IPCs is a key step in determining overall neuronal production and may underlie evolutionary expansion of the cerebral cortex. Here we show that this transition is controlled by fragile X mental retardation protein (FMRP), an RNA-binding protein whose deficiency causes fragile X syndrome. Analysis of mouse embryos electroporated with FMRP small hairpin RNA and knock-out mouse embryos lacking FMRP reveals that specific loss of FMRP causes depletion of neocortical RGCs due to an RGC-to-IPC cell fate change. The RGC depletion is associated with altered F-actin organization and can be largely rescued by overexpressing profilin 1 (Pfn1), a core actin regulatory protein promoting F-actin formation. Our data suggest that FMRP suppresses the transition from RGCs to IPCs during neocortical development by an actin-dependent mechanism.

Inclusion Body Formation and Neurodegeneration Are Parkin Independent in a Mouse Model of α-Synucleinopathy

Abstract: Mutations in the genes coding for α-synuclein and parkin cause autosomal-dominant and autosomal-recessive forms of Parkinson9s disease (PD), respectively. α-Synuclein is a major component of Lewy bodies, the proteinaceous cytoplasmic inclusions that are the pathological hallmark of idiopathic PD. Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin. Parkin is an ubiquitin E3 ligase, and it may be involved in the processing and/or degradation of α-synuclein, as well as in the formation of Lewy bodies. Here we report the behavioral, biochemical, and histochemical characterization of double-mutant mice overexpressing mutant human A53T α-synuclein on a parkin null background. We find that the absence of parkin does not have an impact on the onset and progression of the lethal phenotype induced by overexpression of human A53T α-synuclein. Furthermore, all major behavioral, biochemical, and morphological characteristics of A53T α-synuclein-overexpressing mice are not altered in parkin null α-synuclein-overexpressing double-mutant mice. Our results demonstrate that mutant α-synuclein induces neurodegeneration independent of parkin-mediated ubiquitin E3 ligase activity in nondopaminergic systems and suggest that PD caused by α-synuclein and parkin mutations may occur via independent mechanisms.

Microbial survival of space vacuum and extreme ultraviolet irradiation: strain isolation and analysis during a rocket flight

Abstract: We have recovered new isolates from hot springs, in Yellowstone National Park and the Kamchatka Peninsula, after γ-irradiation and exposure to high vacuum (10−6 Pa) of the water and sediment samples The resistance to desiccation and ionizing radiation of one of the isolates, Bacillus sp strain PS3D, was compared to that of the mesophilic bacterium, Deinococcus radiodurans, a species well known for its extraordinary resistance to desiccation and high doses of ionizing radiation Survival of these two microorganisms was determined in real and simulated space conditions, including exposure to extreme UV radiation (10–100 nm) during a rocket flight We found that up to 15 days of desiccation alone had little effect on the viability of either bacterium In contrast, exposure to space vacuum (∼10−6 Pa) decreased cell survival by two and four orders of magnitude for Bacillus sp strain PS3D and D radiodurans, respectively Simultaneous exposure to space vacuum and extreme UV radiation further decreased the survival of both organisms, compared to unirradiated controls This is the first report on the isolated effect of extreme UV at 30 nm on cell survival Extreme UV can only be transmitted through high vacuum, therefore its penetration into the cells may only be superficial, suggesting that in contrast to near UV, membrane proteins rather than DNA were damaged by the radiation

Analysis of COVID-19 Cases' Spatial Dependence in US Counties Reveals Health Inequalities.

Abstract: On March 13, 2020, the World Health Organization (WHO) declared the 2019 coronavirus disease (COVID-19) caused by the novel coronavirus SARS-CoV2 a pandemic. Since then the virus has infected over 9.1 million individuals and resulted in over 470,000 deaths worldwide (as of June 24, 2020). Here, we discuss the spatial correlation between county population health rankings and the incidence of COVID-19 cases and COVID-19 related deaths in the United States. We analyzed the spread of the disease based on multiple variables at the county level, using publicly available data on the numbers of confirmed cases and deaths, intensive care unit beds and socio-demographic, and healthcare resources in the U.S. Our results indicate substantial geographical variations in the distribution of COVID-19 cases and deaths across the US counties. There was significant positive global spatial correlation between the percentage of Black Americans and cases of COVID-19 (Moran I = 0.174 and 0.264, p < 0.0001). A similar result was found for the global spatial correlation between the percentage of Black American and deaths due to COVID-19 at the county level in the U.S. (Moran I = 0.264, p < 0.0001). There was no significant spatial correlation between the Hispanic population and COVID-19 cases and deaths; however, a higher percentage of non-Hispanic white was significantly negatively spatially correlated with cases (Moran I = -0.203, p < 0.0001) and deaths (Moran I = -0.137, p < 0.0001) from the disease. This study showed significant but weak spatial autocorrelation between the number of intensive care unit beds and COVID-19 cases (Moran I = 0.08, p < 0.0001) and deaths (Moran I = 0.15, p < 0.0001), respectively. These findings provide more detail into the interplay between the infectious disease and healthcare-related characteristics of the population. Only by understanding these relationships will it be possible to mitigate the rate of spread and severity of the disease.

Expanding insights of mitochondrial dysfunction in Parkinson's disease

Abstract: The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.

Parkinson's Disease: Genetics and Pathogenesis

Abstract: Recent investigation into the mechanisms of Parkinson's disease (PD) has generated remarkable insight while simultaneously challenging traditional conceptual frameworks. Although the disease remains defined clinically by its cardinal motor manifestations and pathologically by midbrain dopaminergic cell loss in association with Lewy bodies, it is now recognized that PD has substantially more widespread impact, causing a host of nonmotor symptoms and associated pathology in multiple regions throughout the nervous system. Further, the discovery and validation of PD-susceptibility genes contradict the historical view that environmental factors predominate, and blur distinctions between familial and sporadic disease. Genetic advances have also promoted the development of improved animal models, highlighted responsible molecular pathways, and revealed mechanistic overlap with other neurodegenerative disorders. In this review, we synthesize emerging lessons on PD pathogenesis from clinical, pathological, and gen...