A5022424582- Hereditary Neurological Disorders
- Cannabis and Cannabinoid Research
- Neuroscience and Neuropharmacology Research
- Cellular transport and secretion
- Epilepsy research and treatment
- Autophagy in Disease and Therapy
- Pancreatic function and diabetes
- Neurological diseases and metabolism
- Endoplasmic Reticulum Stress and Disease
- Glycosylation and Glycoproteins Research
- Diet and metabolism studies
- Neurogenetic and Muscular Disorders Research
- Calpain Protease Function and Regulation
- Cellular Mechanics and Interactions
- Metabolism and Genetic Disorders
Boston Children's Hospital
2020-2024
Harvard University
2020-2024
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 neurodegenerative disorder. Here we identify DAGLB (diacylglycerol lipase-beta), key enzyme generation of the endocannabinoid 2-AG (2-arachidonoylglycerol), as cargo vesicles. During normal development, targeted to axon, where signalling drives growth. We show that accumulates at trans-Golgi network cells, levels are reduced...
Abstract 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 identify molecules that correct aberrant protein trafficking adapter complex 4 (AP-4) deficiency, but prototypical form of childhood-onset hereditary spastic paraplegia characterized by mislocalization autophagy ATG9A. Using high-content microscopy and an automated image analysis pipeline,...
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. SSADHD leads to impaired GABA metabolism results in accumulation of γ-hydroxybutyrate (GHB), which alter neurotransmission are thought lead neurobehavioral symptoms. However, why increased inhibitory neurotransmitters seizures remains unclear. We used induced pluripotent stem cells from patients (one female two male) differentiated them into...
Adaptor protein complex 4-associated hereditary spastic paraplegia is caused by biallelic loss-of-function variants in
Biallelic loss-of-function variants in the subunits of adaptor protein complex 4 lead to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1), and SPG52 (AP4S1). Here, we describe generation induced pluripotent stem cells (iPSCs) from three AP-4-HSP patients with biallelic, AP4M1 their sex-matched parents (asymptomatic, heterozygous carriers). Following reprogramming using non-integrating Sendai virus, iPSCs were characterized following...
Abstract 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 novel variants remains challenging, particularly missense mutations. Where sufficient knowledge protein function and/or downstream pathways exists, functional studies patient‐derived cells can aid molecular findings. We here illustrate case a 13‐year‐old female who...
Abstract CAPN1 ‐associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain‐1 function. Here we illustrate translational approach the case an 18‐year‐old patient who first presented with psychiatric symptoms followed by gait, intention tremor, neurogenic bladder dysfunction, consistent complex form HSP. Exome sequencing showed compound‐heterozygous missense variants in (NM_001198868.2: c.1712A>G (p.Asn571Ser)/c.1991C>T...
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 identify molecules that correct aberrant protein trafficking adaptor complex 4 (AP-4) deficiency, but prototypical form of childhood-onset hereditary spastic paraplegia, characterized by mislocalization autophagy ATG9A. Using high-content microscopy and an automated image analysis...
Abstract The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurological disorder, which encompasses neurodevelopmental neurodegenerative features. While impaired autophagy has been suggested to account degeneration in deficiency, growth defects occur through an unknown mechanism. Here we use orthogonal proteomic imaging methods identify DAGLB (diacylglycerol lipase-beta) as cargo of vesicles....
Background/Purpose: Adaptor protein complex 4-associated hereditary spastic paraplegia (AP-4-HSP) is caused by biallelic loss-of-function variants in AP4B1, AP4M1, AP4E1, or AP4S1 which constitute the four subunits of this obligate complex. While diagnosis AP-4-HSP relies on molecular testing, interpretation novel missense remains challenging. Here we address diagnostic gap using patient-derived fibroblasts to establish a functional assay that measures subcellular localization ATG9A,...