M. L. ZIEGLER

CRISPR/Cas9 loss-of-function screen in a neuronal model of AP-4 deficiency identifies ATG9A trafficking modulators

M. L. ZIEGLER, Cedric Günter, Julian E. Alecu, Xutong Xue et autres

Biallelic loss-of-function variants in adaptor protein complex 4 (AP-4) disrupt trafficking of transmembrane proteins at the trans-Golgi network, including autophagy-related protein 9A (ATG9A), leading to childhood-onset hereditary spastic paraplegia (AP-4-HSP). AP-4-HSP is characterized by features of both a neurodevelopmental and a degenerative …

us, de, gb (code pays fourni par la source)

Arrayed CRISPR/Cas9 Loss-Of-Function Screen in a Neuronal Model of Adaptor Protein Complex 4 Deficiency Identifies Modulators of ATG9A Trafficking

M. L. ZIEGLER, Cedric Böger, Julian E. Alecu, Hyo‐Min Kim et autres

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 hereditary spastic paraplegia (AP-4-HSP). AP-4-HSP is characterized by features of both a …

us, de, gb (code pays fourni par la source)

Arrayed CRISPR/Cas9 Loss-of-Function Screen in a Neuronal Model of Adaptor Protein Complex 4 Deficiency Identifies Modulators of ATG9A Trafficking

M. L. ZIEGLER, Cedric Boeger, Julian E. Alecu, Hyo‐Min Kim et autres

us, gb (code pays fourni par la source)

High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia

Afshin Saffari, Barbara Brechmann, Cedric Böger, Wardiya Afshar Saber et autres

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 protein trafficking in adapter protein complex 4 (AP-4) deficiency, a …

us, de, gb (code pays fourni par la source)

High-Content Screening Identifies A Small Molecule That Restores AP-4-dependent Protein Trafficking In Neuronal Models Of AP-4-Associated Hereditary Spastic Paraplegia

Afshin Saffari, Barbara Brechmann, Cedric Böger, Wardiya Afshar Saber et autres

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

Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4‐Related Hereditary Spastic Paraplegia

Julian E. Alecu, Afshin Saffari, M. L. ZIEGLER, Catherine Jordan et autres

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 in AP-4-HSP. METHODS: Plasma neurofilament light chain (pNfL) and glial …

us, de, ca, pl, gb, it (code pays fourni par la source)

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

Afshin Saffari, Barbara Brechmann, Cedric Boeger, Wardiya Afshar Saber et autres

Abstract 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 aberrant protein trafficking in adaptor protein complex 4 (AP-4) …

us, de (code pays fourni par la source)

Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies

Xin Chen, Thomas Z. Dong, Yuhui Hu, Raffaella De Pace et autres

Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global developmental delay, and subsequent intellectual disability, secondary microcephaly, and epilepsy. We preformed preclinical studies evaluating …

us (code pays fourni par la source)

Functional validation of novel variants in B4GALNT1 associated with early‐onset complex hereditary spastic paraplegia with impaired ganglioside synthesis

Julian E. Alecu, Yuhsuke Ohmi, Robiul Hasan Bhuiyan, Kei‐ichiro Inamori et autres

Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein …

us, jp, bd, au (code pays fourni par la source)

Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4 – associated Hereditary Spastic Paraplegia Reveals Patterns for Diagnosis and Disease Progression (S39.010)

Darius Ebrahimi‐Fakhari, Julian E. Alecu, M. L. ZIEGLER, Afshin Saffari et autres

This study aims to define the spectrum of brain MRI findings in AP-4-associated hereditary spastic paraplegia (AP-4-HSP) and to investigate radio-clinical correlations.

us (code pays fourni par la source)

Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early‐onset psychosis

Julian E. Alecu, Afshin Saffari, Hellen Jumo, M. L. ZIEGLER et autres

CAPN1-associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain-1 function. Here we illustrate a translational approach to the case of an 18-year-old patient who first presented with psychiatric symptoms followed by spastic gait, intention …

us (code pays fourni par la source)

AP-4-mediated axonal transport controls endocannabinoid production in neurons

Alexandra K. Davies, Julian E. Alecu, M. L. ZIEGLER, Catherine G. Vasilopoulou et autres

The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurodevelopmental and neurodegenerative disorder. Here we identify DAGLB (diacylglycerol lipase-beta), a key enzyme for generation of the endocannabinoid 2-AG (2-arachidonoylglycerol), as …

de, us, it (code pays fourni par la source)