INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH

Brain ◽  
2021 ◽  
Author(s):  
Denisa Hathazi ◽  
Dan Cox ◽  
Adele D'Amico ◽  
Giorgio Tasca ◽  
Richard Charlton ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Molecular Level ◽  
Proteomic Profiling ◽  
Molecular Feature ◽  
Neuronal Phenotype ◽  
Neurological Phenotype ◽  
Phenotypical Feature ◽  
Human Disorder ◽  
Phosphoglycerate Dehydrogenase ◽  
Biallelic Mutations

Abstract Marinesco-Sjögren syndrome (MSS) is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms that are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between MSS and the INPP5K-phenotype. We applied unbiased proteomic profiling on cells derived from MSS- and INPP5K-patients and identified alterations in D-3-phosphoglycerate dehydrogenase as a common molecular feature. D-3-phosphoglycerate dehydrogenase modulates the production of L-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with MSS and INPP5K-disease. As, L-serine administration represents a promising therapeutic strategy for D-3-phosphoglycerate dehydrogenase patients, we tested the effect of L-serine in generated sil1, phgdh and inpp5k a + b zebrafish models which showed an improvement in their neuronal phenotype. Thus our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

scholarly journals P.133 Expanding the phenotype of TRNT1 mutations to include Leigh syndrome

2018 ◽  
Vol 45 (s2) ◽  
pp. S51-S51
Author(s):  
C Gorodetsky ◽  
CF Morel ◽  
I Tein
Keyword(s):  
Developmental Delay ◽  
Early Adulthood ◽  
Leigh Syndrome ◽  
Global Developmental Delay ◽  
High Dose ◽  
Sideroblastic Anemia ◽  
Whole Exome ◽  
Mitochondrial Transfer ◽  
Neurological Phenotype ◽  
Biallelic Mutations

Background: Children with biallelic mutations in TRNT1 have multi-organ involvement with congenital sideroblastic anemia, -B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) as well as seizures, ataxia and sensorineural hearing loss. The TRNT1 gene encodes the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs accounting for phenotypic pleitropy. Neurodegenerative Leigh syndrome has not been previously reported. Methods:Case summary: A Portuguese boy presented with global developmental delay, 2 episodes of infantile Leigh encephalopathy at 8 mo and 4 yr responsive to high-dose steroids, slow neurodegeneration of cognitive, language and motor functions with optic atrophy, pigmentary retinopathy, spasticity, dystonia, and focal dyscognitive seizures, pancytopenia, transfusion dependent sideroblastic anemia, recurrent febrile infections (pulmonary, gastrointestinal), hypernatremia, with tracheostomy dependence at age 5 yr, malabsorption and TPN dependence at 9 yr, and survival to early adulthood. Neuroimaging showed symmetric hemorrhagic lesions in the thalamus, brain stem (periaqueductal grey) and cerebellum consistent with Leigh syndrome but no lactate peak on MRS. Results: Whole exome sequencing identified a homozygous missense pathogenic variant in TRNT1, c.668T>C (p.I223T) in the affected individual. Conclusions: This report expands the neurological phenotype of TRNT1 mutations and highlights the importance of considering this gene in the evaluation of Leigh syndrome.

scholarly journals Endocannabinoid and dopaminergic system: the pas de deux underlying human motivation and behaviors

2021 ◽  
Author(s):  
A. A. A. Putri Laksmidewi ◽  
Andreas Soejitno
Keyword(s):  
Therapeutic Strategy ◽  
Dopaminergic System ◽  
Molecular Level ◽  
Endocannabinoid System ◽  
Work Related ◽  
Signaling Mechanisms ◽  
Self Actualization ◽  
Individual Survival ◽  
Neurobehavioral Manifestations ◽  
Endogenous Cannabinoid

AbstractEndocannabinoid system (ECS) has been identified ever since cannabinoid, an active substance of Cannabis, was known to interact with endogenous cannabinoid (endocannabinoid/eCB) receptors. It later turned out that eCB was more intricate than previously thought. It has a pervasive role and exerts a multitude of cellular signaling mechanisms, regulating various physiological neurotransmission pathways in the human brain, including the dopaminergic (DA) system. eCB roles toward DA system were robust, clearly delineated, and reproducible with respect to physiological as well as pathological neurochemical and neurobehavioral manifestations of DA system, particularly those involving the nigrostriatal and mesocorticolimbic pathways. The eCB–DA system regulates the basics in the Maslow’s pyramid of hierarchy of needs required for individual survival such as food and sexual activity for reproductive purpose to those of higher needs in the pyramid, including self-actualization behaviors leading to achievement and reward (e.g., academic- and/or work-related performance and achievements). It is, thus, interesting to specifically discuss the eCB–DA system, not only on the molecular level, but also its tremendous potential to be developed as a future therapeutic strategy for various neuropsychiatric problems, including obesity, drug addiction and withdrawal, pathological hypersexuality, or low motivation behaviors.

scholarly journals Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Mara Gagliardi ◽  
Diego Cotella ◽  
Claudio Santoro ◽  
Davide Corà ◽  
Nickolai A. Barlev ◽  
...  
Keyword(s):  
Er Stress ◽  
Metastatic Melanoma ◽  
Therapeutic Strategy ◽  
Molecular Level ◽  
Lipid Peroxides ◽  
Melanoma Cells ◽  
Cross Resistance ◽  
Independent Manner ◽  
Valuable Marker ◽  
Braf Melanoma

AbstractThe incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side effects such as autoimmune disorders could limit its clinical use. Alternative therapeutic strategies are therefore urgently needed to efficiently kill melanoma cells. Ferroptosis induction and execution were evaluated in metastasis-derived wild-type and oncogenic BRAF melanoma cells, and the process responsible for the resistance has been dissected at molecular level. Although efficiently induced in all cells, in an oncogenic BRAF- and ER stress-independent way, most cells were resistant to ferroptosis execution. At molecular level we found that: resistant cells efficiently activate NRF2 which in turn upregulates the early ferroptotic marker CHAC1, in an ER stress-independent manner, and the aldo-keto reductases AKR1C1 ÷ 3 which degrades the 12/15-LOX-generated lipid peroxides thus resulting in ferroptotic cell death resistance. However, inhibiting AKRs activity/expression completely resensitizes resistant melanoma cells to ferroptosis execution. Finally, we found that the ferroptotic susceptibility associated with the differentiation of melanoma cells cannot be applied to metastatic-derived cells, due to the EMT-associated gene expression reprogramming process. However, we identified SCL7A11 as a valuable marker to predict the susceptibility of metastatic melanoma cells to ferroptosis. Our results identify the use of pro-ferroptotic drugs coupled to AKRs inhibitors as a new valuable strategy to efficiently kill human skin melanoma cells.

scholarly journals KRIBB11 Induces Apoptosis in A172 Glioblastoma Cells via MULE-Dependent Degradation of MCL-1

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4165
Author(s):  
Kyunghyun Yoo ◽  
Hye-Hyeon Yun ◽  
Soon-Young Jung ◽  
Jeong-Hwa Lee
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Strategy ◽  
Anticancer Agent ◽  
Molecular Level ◽  
Constitutive Activity ◽  
Glioblastoma Cells ◽  
Essential Step ◽  
Apoptotic Protein ◽  
Induction Of Apoptosis ◽  
A172 Glioma Cells

KRIBB11, an HSF1 inhibitor, was shown to sensitize various types of cancer cells to treatment with several anticancer drugs. However, the exclusive effects of KRIBB11 in preventing the growth of glioblastoma cells and the related mechanisms have not been elucidated yet. Herein, we aimed to examine the potential of KRIBB11 as an anticancer agent for glioblastoma. Using MTT and colony formation assays and Western blotting for c-PARP, we demonstrated that KRIBB11 substantially inhibits the growth of A172 glioma cells by inducing apoptosis. At the molecular level, KRIBB11 decreased anti-apoptotic protein MCL-1 levels, which was attributable to the increase in MULE ubiquitin ligase levels. However, the constitutive activity of HSF1 in A172 cells was not influenced by the exclusive treatment with KRIBB11. Additionally, based on cycloheximide chase assay, we found that KRIBB11 markedly retarded the degradation of MULE. In conclusion, stabilization of MULE upon KRIBB11 treatment is apparently an essential step for degradation of MCL-1 and the subsequent induction of apoptosis in A172 cells. Our results have expanded the knowledge on molecular pathways controlled by KRIBB11 and could be potentially effective for developing an inhibitory therapeutic strategy for glioblastoma.

scholarly journals The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

2020 ◽  
Author(s):  
Thomas D. Jackson ◽  
Daniella Hock ◽  
Catherine S. Palmer ◽  
Yilin Kang ◽  
Kenji M. Fujihara ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Proteomic Profiling ◽  
Inner Mitochondrial Membrane ◽  
Molecular Feature ◽  
Lipid Kinase ◽  
Skeletal Myopathy ◽  
Metabolism Enzymes ◽  
A Subunit ◽  
Sengers Syndrome ◽  
One Carbon Metabolism

AbstractThe Acylglycerol Kinase (AGK) is a mitochondrial lipid kinase that contributes to protein biogenesis as a subunit of the TIM22 complex at the inner mitochondrial membrane. Mutations in AGK cause Sengers syndrome, an autosomal recessive condition characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. We undertook proteomic profiling of Sengers patient fibroblasts and an AGKKO cell line to map the proteomic changes that ensue upon AGK dysfunction. This uncovered extensive remodelling of mitochondrial one-carbon metabolism enzymes and showed that inner membrane serine transporters, Sideroflexins (SFXNs), are novel substrates of the TIM22 complex. Deletion of SFXN1 recapitulates the remodelling of one-carbon metabolism observed in Sengers patient cells. Proliferation of cells lacking AGK is perturbed in the absence of exogenous serine and rescuable through addition of formate, highlighting the dysregulation of one carbon metabolism as a key molecular feature in the biology of Sengers syndrome.

scholarly journals Single-cell Proteomic Profiling Identifies Combined AXL and JAK1 Inhibition as a Novel Therapeutic Strategy for Lung Cancer

2020 ◽  
pp. canres.3183.2019 ◽  
Author(s):  
Josephine A Taverna ◽  
Chia-Nung Hung ◽  
Daniel T DeArmond ◽  
Meizhen Chen ◽  
Chun-Lin Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Single Cell ◽  
Therapeutic Strategy ◽  
Proteomic Profiling ◽  
Novel Therapeutic

Preparatory Procedures for Electron Microscopic Analysis at the Molecular Level of Resolution

1978 ◽  
Vol 36 (3) ◽  
pp. 516-520
Author(s):  
F.J. Sjostrand
Keyword(s):  
Electron Microscope ◽  
Molecular Level ◽  
Microscopic Analysis ◽  
Resolving Power ◽  
Cellular Structures ◽  
Electron Microscopic ◽  
Systematic Analysis ◽  
Technical Developments ◽  
Thin Sectioning ◽  
Obvious Reason

In the 1940's and 1950's electron microscopy conferences were attended with everybody interested in learning about the latest technical developments for one very obvious reason. There was the electron microscope with its outstanding performance but nobody could make very much use of it because we were lacking proper techniques to prepare biological specimens. The development of the thin sectioning technique with its perfectioning in 1952 changed the situation and systematic analysis of the structure of cells could now be pursued. Since then electron microscopists have in general become satisfied with the level of resolution at which cellular structures can be analyzed when applying this technique. There has been little interest in trying to push the limit of resolution closer to that determined by the resolving power of the electron microscope.

RNA polymerase: Preparation and structural analysis of helical polymers

1984 ◽  
Vol 42 ◽  
pp. 152-153
Author(s):  
E. Loren Buhle ◽  
Pamela Rew ◽  
Ueli Aebi
Keyword(s):  
Structural Analysis ◽  
Rna Polymerase ◽  
Molecular Level ◽  
X Ray Diffraction ◽  
Helical Polymers ◽  
X Ray ◽  
E Coli ◽  
The Past ◽  
Ordered Arrays ◽  
Low Ionic Strength

While DNA-dependent RNA polymerase represents one of the key enzymes involved in transcription and ultimately in gene expression in procaryotic and eucaryotic cells, little progress has been made towards elucidation of its 3-D structure at the molecular level over the past few years. This is mainly because to date no 3-D crystals suitable for X-ray diffraction analysis have been obtained with this rather large (MW ~500 kd) multi-subunit (α2ββ'ζ). As an alternative, we have been trying to form ordered arrays of RNA polymerase from E. coli suitable for structural analysis in the electron microscope combined with image processing. Here we report about helical polymers induced from holoenzyme (α2ββ'ζ) at low ionic strength with 5-7 mM MnCl2 (see Fig. 1a). The presence of the ζ-subunit (MW 86 kd) is required to form these polymers, since the core enzyme (α2ββ') does fail to assemble into such structures under these conditions.

The Current Situation in Chemical Stabilization of Biological Materials

1972 ◽  
Vol 30 ◽  
pp. 132-133
Author(s):  
John H. Luft
Keyword(s):  
Electron Microscopy ◽  
Electron Microscope ◽  
Osmium Tetroxide ◽  
Molecular Level ◽  
Cross Linking ◽  
Chemical Stabilization ◽  
Specimen Preparation ◽  
Sufficient Condition ◽  
Radio Telescopes

With information processing devices such as radio telescopes, microscopes or hi-fi systems, the quality of the output often is limited by distortion or noise introduced at the input stage of the device. This analogy can be extended usefully to specimen preparation for the electron microscope; fixation, which initiates the processing sequence, is the single most important step and, unfortunately, is the least well understood. Although there is an abundance of fixation mixtures recommended in the light microscopy literature, osmium tetroxide and glutaraldehyde are favored for electron microscopy. These fixatives react vigorously with proteins at the molecular level. There is clear evidence for the cross-linking of proteins both by osmium tetroxide and glutaraldehyde and cross-linking may be a necessary if not sufficient condition to define fixatives as a class.

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