Stephen C. Pak
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View article: ATG-3 limits Orsay virus infection in C. elegans and regulates collagen pathways
ATG-3 limits Orsay virus infection in C. elegans and regulates collagen pathways Open
Autophagy is an essential cellular process which functions to maintain homeostasis in response to stressors such as starvation or infection. Here, we report that a subset of autophagy factors including ATG-3 play an antiviral role in Orsay…
View article: Sequelae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons
Sequelae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons Open
How aging of human neurons affects dynamics of essential organelle such as mitochondria and autophagosomes remains largely unknown. MicroRNA-induced directly reprogrammed neurons (miNs) derived from adult fibroblasts retain age-associated …
View article: Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders
Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders Open
ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, …
View article: Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders
Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders Open
ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, …
View article: Sequence variants in HECTD1 result in a variable neurodevelopmental disorder
Sequence variants in HECTD1 result in a variable neurodevelopmental disorder Open
Dysregulation of genes encoding the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases has been linked to cancer and structural birth defects. One member of this family, the HECT-domain-containing protein 1 (HECTD1), mediates develo…
View article: ATG-3 limits Orsay virus infection in <i>C. elegans</i> through regulation of collagen pathways
ATG-3 limits Orsay virus infection in <i>C. elegans</i> through regulation of collagen pathways Open
Autophagy is an essential cellular process which functions to maintain homeostasis in response to stressors such as starvation or infection. Here, we report that a subset of autophagy factors including ATG-3 play an antiviral role in Orsay…
View article: Brain malformations and seizures by impaired chaperonin function of TRiC
Brain malformations and seizures by impaired chaperonin function of TRiC Open
Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individual…
View article: Autophagic enhancer rescues Tau accumulation in a stem cell model of frontotemporal dementia
Autophagic enhancer rescues Tau accumulation in a stem cell model of frontotemporal dementia Open
Tau degradation is disrupted in neurodegenerative tauopathies, such as frontotemporal dementia (FTD), which may contribute to Tau aggregation. The prevailing hypothesis has been that Tau degradation is stymied due to an imbalance in proteo…
View article: A fluorescent reporter for rapid assessment of autophagic flux reveals unique autophagy signatures during <i>C. elegans</i> post-embryonic development and identifies compounds that modulate autophagy
A fluorescent reporter for rapid assessment of autophagic flux reveals unique autophagy signatures during <i>C. elegans</i> post-embryonic development and identifies compounds that modulate autophagy Open
Autophagy is important for many physiological processes; and disordered autophagy can contribute to the pathogenesis of a broad range of systemic disorders. C. elegans is a useful model organism for studying the genetics of autophagy, howe…
View article: Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency
Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency Open
Background and Aims: In the classical form of α1-antitrypsin deficiency, a misfolded variant α1-antitrypsin Z accumulates in the endoplasmic reticulum of liver cells and causes liver cell injury by gain-of-function proteotoxicity in a sub-…
View article: Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability
Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability Open
Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is on…
View article: Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling
Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling Open
Background Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identi…
View article: Longitudinal modeling of human neuronal aging identifies RCAN1-TFEB pathway contributing to neurodegeneration of Huntington’s disease
Longitudinal modeling of human neuronal aging identifies RCAN1-TFEB pathway contributing to neurodegeneration of Huntington’s disease Open
Aging is a common risk factor in neurodegenerative disorders and the ability to investigate aging of neurons in an isogenic background would facilitate discovering the interplay between neuronal aging and onset of neurodegeneration. Here, …
View article: <i>SPTSSA</i> variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia
<i>SPTSSA</i> variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia Open
Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-li…
View article: Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay
Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay Open
We describe a proband evaluated through the Undiagnosed Diseases Network (UDN) who presented with microcephaly, developmental delay, and refractory epilepsy with a de novo p.Ala47Thr missense variant in the protein phosphatase gene, PPP5C.…
View article: A dominant negative variant of <i>RAB5B</i> disrupts maturation of surfactant protein B and surfactant protein C
A dominant negative variant of <i>RAB5B</i> disrupts maturation of surfactant protein B and surfactant protein C Open
Significance The Rab5 GTPase functions in early endosome (EE) fusion in the endocytic pathway. Here, we propose that RAB5B also has a noncanonical vesicular fusion function in the regulated secretion pathway that produces mature surfactant…
View article: Functional analysis of a novel <i>de novo</i> variant in <i>PPP5C</i> associated with microcephaly, seizures, and developmental delay
Functional analysis of a novel <i>de novo</i> variant in <i>PPP5C</i> associated with microcephaly, seizures, and developmental delay Open
We describe a proband evaluated through the Undiagnosed Diseases Network (UDN) who presented with microcephaly, developmental delay, and refractory epilepsy with a de novo p.Ala47Thr missense variant in the protein phosphatase gene, PPP5C …
View article: The squamous cell carcinoma antigen/SERPINB3 protects cervical cancer cells from chemoradiation by preventing lysoptosis
The squamous cell carcinoma antigen/SERPINB3 protects cervical cancer cells from chemoradiation by preventing lysoptosis Open
The endogenous lysosomal cysteine protease inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) is elevated in patients with cervical cancer and other malignancies. High serum SERPINB3 is prognostic for recurrence and death follow…