Afshin Saffari
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View article: Mutations in the Key Autophagy Tethering Factor <scp>EPG5</scp> Link Neurodevelopmental and Neurodegenerative Disorders Including Early‐Onset Parkinsonism
Mutations in the Key Autophagy Tethering Factor <span>EPG5</span> Link Neurodevelopmental and Neurodegenerative Disorders Including Early‐Onset Parkinsonism Open
Objective Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating v…
View article: Arrayed CRISPR/Cas9 Loss-Of-Function Screen in a Neuronal Model of Adaptor Protein Complex 4 Deficiency Identifies Modulators of ATG9A Trafficking
Arrayed CRISPR/Cas9 Loss-Of-Function Screen in a Neuronal Model of Adaptor Protein Complex 4 Deficiency Identifies Modulators of ATG9A Trafficking Open
SUMMARY Biallelic loss-of-function variants in the adaptor protein complex 4 (AP-4) disrupt trafficking of transmembrane proteins at the trans -Golgi network, including the autophagy-related protein 9A (ATG9A), leading to childhood-onset h…
View article: Long-term neuropsychologic outcome of pre-emptive mTOR inhibitor treatment in children with tuberous sclerosis complex (TSC) under 4 months of age (PROTECT), a two-arm, randomized, observer-blind, controlled phase IIb national multicentre clinical trial: study protocol
Long-term neuropsychologic outcome of pre-emptive mTOR inhibitor treatment in children with tuberous sclerosis complex (TSC) under 4 months of age (PROTECT), a two-arm, randomized, observer-blind, controlled phase IIb national multicentre clinical trial: study protocol Open
Background Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting multiple organ systems, with a prevalence of 1:6,760–1:13,520 live births in Germany. On the molecular level, TSC is caused by heterozygous los…
View article: Arrayed CRISPR/Cas9 Loss-of-Function Screen in a Neuronal Model of Adaptor Protein Complex 4 Deficiency Identifies Modulators of ATG9A Trafficking
Arrayed CRISPR/Cas9 Loss-of-Function Screen in a Neuronal Model of Adaptor Protein Complex 4 Deficiency Identifies Modulators of ATG9A Trafficking Open
View article: Identification of Biochemical Determinants for Diagnosis and Prediction of Severity in 5q Spinal Muscular Atrophy Using 1H-Nuclear Magnetic Resonance Metabolic Profiling in Patient-Derived Biofluids
Identification of Biochemical Determinants for Diagnosis and Prediction of Severity in 5q Spinal Muscular Atrophy Using 1H-Nuclear Magnetic Resonance Metabolic Profiling in Patient-Derived Biofluids Open
This study explores the potential of 1H-NMR spectroscopy-based metabolic profiling in various biofluids as a diagnostic and predictive modality to assess disease severity in individuals with 5q spinal muscular atrophy. A total of 213 biosa…
View article: An update on autophagy disorders
An update on autophagy disorders Open
Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post…
View article: Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47
Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47 Open
View article: Biallelic variants in RINT1 present as early-onset pure hereditary spastic paraplegia
Biallelic variants in RINT1 present as early-onset pure hereditary spastic paraplegia Open
View article: Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders
Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders Open
Autophagy is a fundamental and evolutionary conserved biological pathway with vital roles in intracellular quality control and homeostasis. The process of autophagy involves the engulfment of intracellular targets by autophagosomes and the…
View article: The expanding clinical and genetic spectrum of <i>DYNC1H1</i>-related disorders
The expanding clinical and genetic spectrum of <i>DYNC1H1</i>-related disorders Open
Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and interme…
View article: The spectrum of movement disorders in young children with <scp><i>ARX</i></scp>‐related <scp>epilepsy‐dyskinesia</scp> syndrome
The spectrum of movement disorders in young children with <span><i>ARX</i></span>‐related <span>epilepsy‐dyskinesia</span> syndrome Open
Children with developmental and epileptic encephalopathies often present with co‐occurring dyskinesias. Pathogenic variants in ARX cause a pleomorphic syndrome that includes infantile epilepsy with a variety of movement disorders ranging f…
View article: High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia Open
Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant p…
View article: High-Content Screening Identifies A Small Molecule That Restores AP-4-dependent Protein Trafficking In Neuronal Models Of AP-4-Associated Hereditary Spastic Paraplegia
High-Content Screening Identifies A Small Molecule That Restores AP-4-dependent Protein Trafficking In Neuronal Models Of AP-4-Associated Hereditary Spastic Paraplegia Open
Supplementary data of the manuscript: High-Content Small Molecule Screen Identifies a Novel Compound That Restores AP-4-Dependent Protein Trafficking in Neuronal Models of AP-4-Associated Hereditary Spastic Paraplegia
View article: Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex <scp>4‐Related</scp> Hereditary Spastic Paraplegia
Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex <span>4‐Related</span> Hereditary Spastic Paraplegia Open
Background Adaptor protein complex 4‐associated hereditary spastic paraplegia (AP‐4‐HSP) is caused by pathogenic biallelic variants in AP4B1 , AP4M1 , AP4E1, and AP4S1 . Objective The aim was to explore blood markers of neuroaxonal damage …
View article: Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in <i>STXBP1</i>
Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in <i>STXBP1</i> Open
We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and ne…
View article: High-Content Small Molecule Screen Identifies a Novel Compound That Restores AP-4-Dependent Protein Trafficking in Neuronal Models of AP-4-Associated Hereditary Spastic Paraplegia
High-Content Small Molecule Screen Identifies a Novel Compound That Restores AP-4-Dependent Protein Trafficking in Neuronal Models of AP-4-Associated Hereditary Spastic Paraplegia Open
Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect novel therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aber…
View article: Reply to: Early‐Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in <i>SPAST</i>
Reply to: Early‐Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in <i>SPAST</i> Open
Data are available from the corresponding author upon reasonable request.
View article: Supplementary Materials and Methods from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Supplementary Materials and Methods from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Supplementary Materials and Methods
View article: Figure S2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Figure S2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Sod2 overexpression reduces the percentage of MitoSOX positive cells assessed by flow cytometry
View article: Figure S4 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Figure S4 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Regulation of Nrf2 and NFkB by p62 in Tsc2-null cells and tumors
View article: Supplementary Materials and Methods from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Supplementary Materials and Methods from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Supplementary Materials and Methods
View article: Figure S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Figure S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Transcript levels of amino acid transporters and enzymes regulating glutathione biosynthesis
View article: Figure S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Figure S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Transcript levels of amino acid transporters and enzymes regulating glutathione biosynthesis
View article: Figure S4 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Figure S4 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Regulation of Nrf2 and NFkB by p62 in Tsc2-null cells and tumors
View article: Raw data for Supplementary Table 1 and 2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Raw data for Supplementary Table 1 and 2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Raw data and bioinformatic analysis of metabolomics and ion torrent expression profiling
View article: Supplementary Table S2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Supplementary Table S2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Oxidative stress genes regulated by p62
View article: Figure S3 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Figure S3 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
H2DCFDA controls
View article: Supplementary Table S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Supplementary Table S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Metabolites significantly changed by p62 knockdown in Tsc2-/- MEFs
View article: Figure S2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Figure S2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
Sod2 overexpression reduces the percentage of MitoSOX positive cells assessed by flow cytometry
View article: Data from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis
Data from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis Open
p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate that accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes tuberous sclerosis complex (TSC)…