“…1 a). Although which organs/tissues should be therapeutically targeted remain unclear, given the prominent neurological symptoms [ 3 – 10 , 14 ], we evaluated the direct effect of CNS-focused gene delivery to reverse motor dysfunction in Ngly1−/− rats. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Since then, more than 60 similar patients have been confirmed worldwide and several clinical reports have been published [ 4 – 10 ]. NGLY1 deficient patients show a broad spectrum of clinical features including developmental delay, hypolacrima or alacrima, seizure, intellectual disability, and motor deficits [ 4 – 14 ]. The mutant form of Ngly1 and its orthologs have been analyzed to elucidate the molecular function of NGLY1 in various organisms [ 1 , 15 – 31 ].…”
Section: Introductionmentioning
confidence: 99%
“…In addition, it is important to clarify the target organs and cells for the development of therapeutic agents and modalities for NGLY1 deficiency. While Ngly1 is ubiquitously expressed throughout the body with the highest expression in the testis [ 33 ], the neurological symptoms in most patients suggest abnormalities in the CNS [ 4 – 11 , 14 ]. However, it remains unclear whether loss of NGLY1 in the CNS primarily causes the symptoms of NGLY1 deficiency.…”
N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, motor deficits, and other neurological symptoms. The underlying mechanisms of the NGLY1 phenotype are poorly understood, and no effective therapy is currently available. Similar to human patients, the rat model of NGLY1 deficiency, Ngly1−/−, shows developmental delay, movement disorder, somatosensory impairment, scoliosis, and learning disability. Here we show that single intracerebroventricular administration of AAV9 expressing human NGLY1 cDNA (AAV9-hNGLY1) to Ngly1−/− rats during the weaning period restored NGLY1 expression in the brain and spinal cord, concomitant with increased enzymatic activity of NGLY1 in the brain. hNGLY1 protein expressed by AAV9 was found predominantly in mature neurons, but not in glial cells, of Ngly1−/− rats. Strikingly, intracerebroventricular administration of AAV9-hNGLY1 normalized the motor phenotypes of Ngly1−/− rats assessed by the rota-rod test and gait analysis. The reversibility of motor deficits in Ngly1−/− rats by central nervous system (CNS)-restricted gene delivery suggests that the CNS is the primary therapeutic target organs for NGLY1 deficiency, and that the Ngly1−/− rat model may be useful for evaluating therapeutic treatments in pre-clinical studies.
“…1 a). Although which organs/tissues should be therapeutically targeted remain unclear, given the prominent neurological symptoms [ 3 – 10 , 14 ], we evaluated the direct effect of CNS-focused gene delivery to reverse motor dysfunction in Ngly1−/− rats. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Since then, more than 60 similar patients have been confirmed worldwide and several clinical reports have been published [ 4 – 10 ]. NGLY1 deficient patients show a broad spectrum of clinical features including developmental delay, hypolacrima or alacrima, seizure, intellectual disability, and motor deficits [ 4 – 14 ]. The mutant form of Ngly1 and its orthologs have been analyzed to elucidate the molecular function of NGLY1 in various organisms [ 1 , 15 – 31 ].…”
Section: Introductionmentioning
confidence: 99%
“…In addition, it is important to clarify the target organs and cells for the development of therapeutic agents and modalities for NGLY1 deficiency. While Ngly1 is ubiquitously expressed throughout the body with the highest expression in the testis [ 33 ], the neurological symptoms in most patients suggest abnormalities in the CNS [ 4 – 11 , 14 ]. However, it remains unclear whether loss of NGLY1 in the CNS primarily causes the symptoms of NGLY1 deficiency.…”
N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, motor deficits, and other neurological symptoms. The underlying mechanisms of the NGLY1 phenotype are poorly understood, and no effective therapy is currently available. Similar to human patients, the rat model of NGLY1 deficiency, Ngly1−/−, shows developmental delay, movement disorder, somatosensory impairment, scoliosis, and learning disability. Here we show that single intracerebroventricular administration of AAV9 expressing human NGLY1 cDNA (AAV9-hNGLY1) to Ngly1−/− rats during the weaning period restored NGLY1 expression in the brain and spinal cord, concomitant with increased enzymatic activity of NGLY1 in the brain. hNGLY1 protein expressed by AAV9 was found predominantly in mature neurons, but not in glial cells, of Ngly1−/− rats. Strikingly, intracerebroventricular administration of AAV9-hNGLY1 normalized the motor phenotypes of Ngly1−/− rats assessed by the rota-rod test and gait analysis. The reversibility of motor deficits in Ngly1−/− rats by central nervous system (CNS)-restricted gene delivery suggests that the CNS is the primary therapeutic target organs for NGLY1 deficiency, and that the Ngly1−/− rat model may be useful for evaluating therapeutic treatments in pre-clinical studies.
“…After comparing the spectrum of clinical phenotypes and histological analysis, Ngly1 −/− rats displayed very similar features with human NGLY1-deficiency patients [72]. Although Ngly1 was ubiquitously expressed, and highly transcribed in brain, lung, heart, kidney, liver, placenta and testis [99], the neurological symptoms in most patients implied CNS be the most seriously affected organ [95].…”
Section: Exogenous Restoration Of Ngly1 Expressionmentioning
The cytosolic PNGase (peptide:N-glycanase; Png1 in yeast; NGLY1/Ngly1 in human/mice), also known as peptide-N4-(N-acetyl-beta-glucosaminyl)-asparagine ami-dase, is a well-conserved deglycosylation enzyme (EC 3.5.1.52) which catalyzes the non-lysosomal hydrolysis of an N(4)-(acetyl-β-D-glucosaminyl) asparagine residue into N-acetyl-β-D-glucosaminylamine and a peptide containing an aspartate residue. This enzyme (NGLY1) plays essential roles in clearance of misfolded or unassembled gly-coproteins through a process named ER-associated degradation (ERAD). Accumulating evidence also points out that NGLY1 deficiency can cause an autosomal recessive hu-man genetic disorder associated with abnormal development and congenital disorder of deglycosylation. In addition, the loss of NGLY1 can affect multiple cellular pathways, including but not limited to NFE2L1 pathway, Creb1/Atf1-AQP pathway, BMP path-way, AMPK pathway, and SLC12A2 ion transporter, which might be the underlying reasons for a constellation of clinical phenotypes of NGLY1 deficiency. The current comprehensive review indeed uncovers the detailed NGLY1’s structure and its im-portant roles for participation in ERAD, involvement in CDDG and potential treatment for NGLY1 deficiency.
“…Symptoms arise in infancy and vary between individual patients. Most patients do not survive past childhood 7,8 and no therapeutic options have been developed thus far. As revealed by whole exome sequencing, the disorder is caused by a mutation in NGLY1 gene which encodes the cytosolic enzyme N-glycanase1 (NGLY1) responsible for protein deglycosylation, a process necessary for the endoplasmic reticulum associated degradation (ERAD) of misfolded or damaged glycoproteins 1,[9][10][11][12] .…”
NGLY1 (N-glycanase 1) deficiency is a rare congenital recessive disorder caused by a mutation in the NGLY1 gene, which encodes the cytosol enzyme N-glycanase 1. The NGLY1 protein catalyzes the first step in protein deglycosylation, a process prerequisite for the cytosolic degradation of misfolded glycoproteins. By performing and combining metabolomics and proteomics profiles, we showed that NGLY1 deficiency induced the activation of immune response, disturbed lipid metabolism, biogenic amine synthesis and glutathione metabolism. The discovery was further validated by profiling of patient-derived induced pluripotent stem cells (iPSCs) and differentiated neural progenitor cells (NPCs), which serve as a personalized cellular model of the disease. This study provides new insights into the NGLY1 deficiency pathology and demonstrates that the upregulation of immune response and downregulation of lipid metabolism appear to be important molecular phenotypes of NGLY1 deficiency, together with the dysregulation of amino acid metabolism, biogenic amine synthesis and diverse signaling pathways, likely causing broad downstream syndromes. Collectively, such valuable multi-omics profiles identified broad molecular associations of potential pathological mechanisms during the onset of NGLY1 deficiency and suggested potential therapeutic targets for researchers and clinicians.
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