Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder.

Sequence variants in the HERC2 gene are associated with a significant reduction in HERC2 protein levels and cause a neurodevelopmental disorder known as the HERC2-related disorder, which shares clinical features with Angelman syndrome, including global developmental delay, intellectual disability, autism, and movement disorders. Remarkably, the HERC2 gene is commonly deleted in individuals with Angelman syndrome, suggesting a potential contribution of HERC2 to the pathophysiology of this disease. Given the known critical role of autophagy in brain development and its implication in neurodevelopmental diseases, we undertook different experimental approaches to monitor autophagy in fibroblasts derived from individuals affected by the HERC2-related disorder. Our findings reveal alterations in the levels of the autophagy-related protein LC3. Furthermore, experiments with lysosomal inhibitors provide confirmation of an upregulation of the autophagy pathway in these patient-derived cells. Mechanistically, we corroborate an interaction between HERC2 and the deubiquitylating enzyme USP20; and demonstrate that HERC2 deficiency leads to increased USP20 protein levels. Notably, USP20 upregulation correlates with enhanced stability of the autophagy initiating kinase ULK1, highlighting the role of HERC2 as an autophagy regulator factor through the USP20-ULK1 axis. Moreover, we show that p38 acts as a modulator of this pathway, since p38 activation disrupts HERC2-USP20 interaction, leading to increased USP20 and LC3-II protein levels. Together, these findings uncover a previously unknown role for HERC2 in autophagy regulation and provide insights into the pathomolecular mechanisms underlying the HERC2-related disorder and Angelman syndrome.

Aceptación y reticencia a las vacunas contra COVID-19 en ingresantes a una universidad pública peruana durante la tercera ola pandémica

Introducción. Los estudiantes universitarios influyen en las decisiones de su familia y comunidad a favor de la vacunación. Objetivo. Identificar las principales razones para la aceptación o reticencia vacunal contra COVID-19 en ingresantes a una universidad pública. Métodos. Estudio transversal en una muestra de 408 estudiantes. Se preguntó si había completado las tres dosis de vacuna contra COVID-19 y la principal razón para la aceptación o reticencia vacunal. Se realizó un análisis descriptivo, se aplicó la prueba chi cuadrado y exacta de Fisher. Resultados. El 85,5% aceptó la vacuna principalmente por no querer contagiar a familiares (38,1%) y no querer enfermarse (27,8%). El 14,5% fue reticente, especialmente por prolongados tiempos de espera en vacunatorios (37,3%) y lejanía de los centros de vacunación (13,6%). Conclusiones. En los universitarios estudiados, el temor a la enfermedad impulsó la aceptación de la vacuna contra COVID-19 y la inaccesibilidad a los servicios de salud generó la reticencia.

Introduction. University students influence their family and community decisions in favor of vaccination. Objective. To identify the main reasons for COVID-19 vaccine acceptance or hesitancy among university entrants. Methods. A cross-sectional study in a sample of 408 students. We asked whether the student had completed the three doses the COVID-19 vaccine and the main reason for vaccine acceptance or hesitancy. A descriptive analysis was performed, the chi-square test and Fisher's exact were applied. Results. 85.5% accepted vaccination mainly because they did not want to infect family members (38.1%) and did not want to get sick (27.8%). 14.5% were hesitancy especially due to long waiting times in vaccination centers (37.3%) and distance from vaccination centers (13.6%). Conclusions. In the university students studied, the fear of disease drove COVID-19 vaccine acceptance and inaccessibility to health services generated vaccine hesitancy among university entrants.

Inhibition of C5AR1 impairs osteoclast mobilization and prevents bone loss.

Age-related and chemotherapy-induced bone loss depends on cellular senescence and the cell secretory phenotype. However, the factors secreted in the senescent microenvironment that contribute to bone loss remain elusive. Here, we report a central role for the inflammatory alternative complement system in skeletal bone loss. Through transcriptomic analysis of bone samples, we identified complement factor D, a rate-limiting factor of the alternative pathway of complement, which is among the most responsive factors to chemotherapy or estrogen deficiency. We show that osteoblasts and osteocytes are major inducers of complement activation, while monocytes and osteoclasts are their primary targets. Genetic deletion of C5ar1, the receptor of the anaphylatoxin C5a, or treatment with a C5AR1 inhibitor reduced monocyte chemotaxis and osteoclast differentiation. Moreover, genetic deficiency or inhibition of C5AR1 partially prevented bone loss and osteoclastogenesis upon chemotherapy or ovariectomy. Altogether, these lines of evidence support the idea that inhibition of alternative complement pathways may have some therapeutic benefit in osteopenic disorders.

Regulation of Ubiquitin Family Signaling in Disease.

Ubiquitin is a small regulatory protein found in all eukaryotic cells [...].

Regulation of MAPK Signaling Pathways by the Large HERC Ubiquitin Ligases.

Protein ubiquitylation acts as a complex cell signaling mechanism since the formation of different mono- and polyubiquitin chains determines the substrate's fate in the cell. E3 ligases define the specificity of this reaction by catalyzing the attachment of ubiquitin to the substrate protein. Thus, they represent an important regulatory component of this process. Large HERC ubiquitin ligases belong to the HECT E3 protein family and comprise HERC1 and HERC2 proteins. The physiological relevance of the Large HERCs is illustrated by their involvement in different pathologies, with a notable implication in cancer and neurological diseases. Understanding how cell signaling is altered in these different pathologies is important for uncovering novel therapeutic targets. To this end, this review summarizes the recent advances in how the Large HERCs regulate the MAPK signaling pathways. In addition, we emphasize the potential therapeutic strategies that could be followed to ameliorate the alterations in MAPK signaling caused by Large HERC deficiencies, focusing on the use of specific inhibitors and proteolysis-targeting chimeras.

HERC1 deficiency causes osteopenia through transcriptional program dysregulation during bone remodeling.

Bone remodeling is a continuous process between bone-forming osteoblasts and bone-resorbing osteoclasts, with any imbalance resulting in metabolic bone disease, including osteopenia. The HERC1 gene encodes an E3 ubiquitin ligase that affects cellular processes by regulating the ubiquitination of target proteins, such as C-RAF. Of interest, an association exists between biallelic pathogenic sequence variants in the HERC1 gene and the neurodevelopmental disorder MDFPMR syndrome (macrocephaly, dysmorphic facies, and psychomotor retardation). Most pathogenic variants cause loss of HERC1 function, and the affected individuals present with features related to altered bone homeostasis. Herc1-knockout mice offer an excellent model in which to study the role of HERC1 in bone remodeling and to understand its role in disease. In this study, we show that HERC1 regulates osteoblastogenesis and osteoclastogenesis, proving that its depletion increases gene expression of osteoblastic makers during the osteogenic differentiation of mesenchymal stem cells. During this process, HERC1 deficiency increases the levels of C-RAF and of phosphorylated ERK and p38. The Herc1-knockout adult mice developed imbalanced bone homeostasis that presented as osteopenia in both sexes of the adult mice. By contrast, only young female knockout mice had osteopenia and increased number of osteoclasts, with the changes associated with reductions in testosterone and dihydrotestosterone levels. Finally, osteocytes isolated from knockout mice showed a higher expression of osteocytic genes and an increase in the Rankl/Opg ratio, indicating a relevant cell-autonomous role of HERC1 when regulating the transcriptional program of bone formation. Overall, these findings present HERC1 as a modulator of bone homeostasis and highlight potential therapeutic targets for individuals affected by pathological HERC1 variants.

Apendicitis aguda y el riesgo de tumor maligno oculto. Presentación de un caso y revisión sistemática de la literatura / Acute appendicitis and the risk of hidden malignant tumor. Presentation of a case and systematic review of literature

Introducción: Los tumores apendiculares representan aproximadamente 1% de los tumores malignos del intestino grueso. Más del 50% de las neoplasias primarias del apéndice se manifiestan inicialmente como apendicitis aguda. Métodos: Se reporta caso de paciente masculino que presentó adenocarcinoma invasor en biopsia de pieza quirúrgica de apéndice cecal tras apendicectomía, tomando la decisión de realizar hemicolectomía derecha laparoscópica diferida. Discusión: En este caso y como en la mayoría de los reportes de la bibliografía mundial, el adenocarcinoma simula un cuadro de AA. En un metaanálisis y una revisión sistemática de 2.771 pacientes diagnosticados de masa apendicular inflamatoria (flemón o absceso), Andersson et al. encontró 31 con tumores malignos. Estas lesiones se detectan en el 0,9% al 1,4% de las apendicectomías realizadas para tratar la AA. Conclusión: Este subtipo histológico presenta mayor incidencia de metástasis en los ganglios linfáticos y la supervivencia global era del 47,5%. Es por ello por lo que abogamos por la resección colónica como tratamiento definitivo del adenocarcinoma de apéndice cecal.

INTRODUCTION: Appendulular tumors represent approximately 1% of malignant tumors of the large intestine. More than 50% of the primary neoplasms of the appendix initially manifest as acute appendicitis. Methods: Men's patient who presented invading adenocarcinoma in Cecal Appendix Surgical Party Biopsy after appendectomy, making the decision to perform deferred laparoscopic right hemicolectomy, is reported. Discussion: In this case and as in most world literature reports, adenocarcinoma simulates an AA picture. In a meta -analysis and a systematic review of 2,771 diagnosed patients of inflammatory appendicular mass (phlegmon or abscess), Andersson et al. He found 31 with malignant tumors. These lesions are detected at 0.9% to 1.4% of appendectomies made to treat the AA. Conclusion: This histological subtype has a greater incidence of metastasis in lymph nodes and global survival was 47.5%. That is why we advocate colonic resection as a definitive treatment of cecal appendix adenocarcinoma.

Revisión Anatómica de Sistema Venoso Intrahepático. Hematoma Intrahepático Subcapsular en Colecistectomia Laparoscópica / Anatomical Review of Intrahepatic Venous System. Subcapsular Intrahepatic Hematoma In Laparoscopic Cholecystectomy

La aparición del hematoma intrahepático subcapsular (SHI) después de la colecistectomía laparoscópica es una complicación poco frecuente. El estudio anatómico de las venas suprahepáticas nos permitió observar que existen numerosos patrones de ramificación de estos. Presentamos el caso de una mujer de 37 años que, durante la intervención de colecistectomía laparoscópica, se observa en el acto quirúrgico, la formación espontánea de hematomas subcapsulares, secundario a la tracción forzada del fondo del órgano

The appearance of subcapsular intrahepatic hematoma (SHI) after laparoscopic cholecystectomy is an infrequent complication.The anatomical study of the suprahepatic veins allowed us to observe that there are numerous branching patterns of these. We present the case of a 37-year-old female who, during the laparoscopic cholecystectomy intervention, is observed in the surgical act, the spontaneous formation of subcapsular hematomas, secondary to forced traction of the fundus of the organ

HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway altering the cellular response to oxidative stress.

HERC2 gene encodes an E3 ubiquitin ligase involved in several cellular processes by regulating the ubiquitylation of different protein substrates. Biallelic pathogenic sequence variants in the HERC2 gene are associated with HERC2 Angelman-like syndrome. In pathogenic HERC2 variants, complete absence or marked reduction in HERC2 protein levels are observed. The most common pathological variant, c.1781C > T (p.Pro594Leu), encodes an unstable HERC2 protein. A better understanding of how pathologic HERC2 variants affect intracellular signalling may aid definition of potential new therapies for these disorders. For this purpose, we studied patient-derived cells with the HERC2 Pro594Leu variant. We observed alteration of mitogen-activated protein kinase signalling pathways, reflected by increased levels of C-RAF protein and p38 phosphorylation. HERC2 knockdown experiments reproduced the same effects in other human and mouse cells. Moreover, we demonstrated that HERC2 and RAF proteins form molecular complexes, pull-down and proteomic experiments showed that HERC2 regulates C-RAF ubiquitylation and we found out that the p38 activation due to HERC2 depletion occurs in a RAF/MKK3-dependent manner. The displayed cellular response was that patient-derived and other human cells with HERC2 deficiency showed higher resistance to oxidative stress with an increase in the master regulator of the antioxidant response NRF2 and its target genes. This resistance was independent of p53 and abolished by RAF or p38 inhibitors. Altogether, these findings identify the activation of C-RAF/MKK3/p38 signalling pathway in HERC2 Angelman-like syndrome and highlight the inhibition of RAF activity as a potential therapeutic option for individuals affected with these rare diseases.

Bezoar. A propósito de un caso / Bezoar. A case report

Introducción: la obstrucción del intestino delgado (SBO) es una presentación común en cualquier unidad de cirugía general. Sin embargo, su diagnóstico y manejo preoperatorio a menudo pueden ser difíciles debido a sus múltiples causas. La obstrucción intestinal pequeña secundaria a la impactación de bezoar es considerablemente infrecuente, con una frecuencia reportada de aproximadamente 0.4% a 4%. La incidencia de bezoar como causa de obstrucción intestinal es baja. El método complementario con la mayor sensibilidad y especificidad continúa siendo CT del abdomen y la pelvis con contraste oral e intravenoso. El tratamiento debe ser quirúrgico. Modificar la dieta junto con el manejo de los trastornos es la mejor forma de prevención.

Introduction: Small Bowel Obstruction (SBO) is a common presentation in any general surgery unit. However, its diagnosis and preoperative management can often be difficult due to its multiple causes. Small bowel obstruction secondary to bezoar impaction is considerably uncommon, with a reported frequency of about 0.4% to 4%. The incidence of bezoar as a cause of intestinal obstruction is low. The complementary method with the highest sensitivity and specificity continues to be CT of the abdomen and pelvis with oral and intravenous contrast. Treatment must be surgical. Modifying the diet along with managing the disorders is the best form of prevention

The HERC proteins and the nervous system.

The HERC protein family is one of three subfamilies of Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases. Six HERC genes have been described in humans, two of which encode Large HERC proteins -HERC1 and HERC2- with molecular weights above 520 kDa that are constitutively expressed in the brain. There is a large body of evidence that mutations in these Large HERC genes produce clinical syndromes in which key neurodevelopmental events are altered, resulting in intellectual disability and other neurological disorders like epileptic seizures, dementia and/or signs of autism. In line with these consequences in humans, two mice carrying mutations in the Large HERC genes have been studied quite intensely: the tambaleante mutant for Herc1 and the Herc2+/530 mutant for Herc2. In both these mutant mice there are clear signs that autophagy is dysregulated, eliciting cerebellar Purkinje cell death and impairing motor control. The tambaleante mouse was the first of these mice to appear and is the best studied, in which the Herc1 mutation elicits: (i) delayed neural transmission in the peripheral nervous system; (ii) impaired learning, memory and motor control; and (iii) altered presynaptic membrane dynamics. In this review, we discuss the information currently available on HERC proteins in the nervous system and their biological activity, the dysregulation of which could explain certain neurodevelopmental syndromes and/or neurodegenerative diseases.

NRF2 function in osteocytes is required for bone homeostasis and drives osteocytic gene expression.

Osteocytes, the most abundant bone cell type, are derived from osteoblasts through a process in which they are embedded in an osteoid. We previously showed that nutrient restriction promotes the osteocyte transcriptional program and is associated with increased mitochondrial biogenesis. Here, we show that increased mitochondrial biogenesis increase reactive oxygen species (ROS) levels and consequently, NRF2 activity during osteocytogenesis. NRF2 activity promotes osteocyte-specific expression of Dmp1, Mepe, and Sost in IDG-SW3 cells, primary osteocytes, and osteoblasts, and in murine models with Nfe2l2 deficiency in osteocytes or osteoblasts. Moreover, ablation of Nfe2l2 in osteocytes or osteoblasts generates osteopenia and increases osteoclast numbers with marked sexual dimorphism. Finally, treatment with dimethyl fumarate prevented the deleterious effects of ovariectomy in trabecular bone masses of mice and restored osteocytic gene expression. Altogether, we uncovered the role of NRF2 activity in osteocytes during the regulation of osteocyte gene expression and maintenance of bone homeostasis.

HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory.

Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning.

[Usefulness of the Difficult Cholecystectomy Score according to laparoscopic conversion]. / Utilidad del Score de la Colecistectomía Dificultosa según conversión laparoscópica.

Introduction: Biliary lithiasis (LB) is a very frequent problem in the daily consultation of a general surgeon, so currently, 10 to 15% of the adult population in the experienced countries has LB. Methodology: A descriptive, observational and cross-sectional study was carried out with patients sometimes having a laparoscopic cholecystectomy in a period between January 1, 2018 and December 31, 2018. The main objective of this study is to determine the differences in the risk scoring means of difficult cholecystectomy according to the conversion to open surgery in patients diagnosed with symptomatic biliary lithiasis. Results: Through the registered data, it can be said that being a man, with a leukocyte count> 12,000 mm3, with a BMI> 30, the presence of choledocholithiasis and a greater gallbladder cut with 3 mm are factors that increase the risk of conversion to open surgery in this series of patients. It is feasible and safe to use this score to determine the patients with the highest risk of conversion since all the independent factors identified are not modifiable. Conclusion: In short, being a man, with a leukocyte count> 10,000 mm3, with a BMI> 30, the presence of choledocholithiasis and a gallbladder wall greater than 3 mm are factors that increase the risk of conversion to open surgery in a series of patients undergoing video laparoscopy. in a university hospital and it is feasible and safe to use this score to identify those patients with the highest risk of conversion.

Introducción: La litiasis biliar (LB) es un problema muy frecuente en la consulta diaria de un cirujano general, por lo que actualmente, del 10 al 15% de la población adulta en los países desarrollados presenta LB. Metodología: Se realizó un estudio descriptivo, observacional y transversal con los pacientes sometidos a colecistectomía laparoscópica en un período comprendido entre el 1 de enero del 2018 y el 31 de diciembre del 2018. El objetivo principal de este estudio es determinar diferencias de media del score de riesgo de colecistectomía dificultosa según conversión a cirugía abierta en pacientes con diagnóstico de litiasis biliar sintomática. Resultados: A través de los datos registrados se puede decir que ser hombre, con recuento de leucocitos >12.000 mm3, con IMC >30, presencia de coledocolitiasis y pared vesicular mayor a 3 mm son factores que incrementan el riesgo de conversión a cirugía abierta en esta serie de pacientes. Es factible y seguro utilizar este score para determinar aquellos pacientes con mayor riesgo de conversión dado que todos los factores independientes identificados no son modificables. Conclusión: En definitiva, ser hombre, con recuento de leucocitos >10.000 mm3, con IMC >30, presencia de coledocolitiasis y pared vesicular mayor a 3 mm son factores que incrementan el riesgo de conversión a cirugía abierta en una serie de pacientes sometidos a video laparoscopía en un Hospital universitario y es factible y seguro utilizar este score para identificar esos pacientes con mayor riesgo de conversión.

A new homozygous HERC1 gain-of-function variant in MDFPMR syndrome leads to mTORC1 hyperactivation and reduced autophagy during cell catabolism.

The giant 532 kDa HERC1 protein is a ubiquitin ligase that interacts with tuberous sclerosis complex subunit 2 (TSC2), a negative upstream regulator of the mammalian target of rapamycin complex 1 (mTORC1). TSC2 regulates anabolic cell growth through its influence on protein synthesis, cell growth, proliferation, autophagy, and differentiation. TSC subunit 1 (TSC1) stabilizes TSC2 by inhibiting the interaction between TSC2 and HERC1, forming a TSC1-TSC2 complex that negatively regulates mTORC1. HERC1-TSC2 interaction destabilizes and degrades TSC2. Recessive mutations in HERC1 have been reported in patients with intellectual disability. Some patients exhibit epilepsy, macrocephaly, somatic overgrowth, and dysmorphic facial features as well. Here we describe two sisters from a consanguineous marriage with a novel homozygous missense variant in the C-terminal HECT domain of HERC1 [chr15:g63,907,989C>G GRCh37.p11 | c.14,072G>C NM_003922 | p.(Arg4,691Pro)]. Symptoms compris global developmental delay, macrocephaly, somatic overgrowth, intellectual disability, seizures, schizoaffective disorder, and pyramidal tract signs. We functionally assessed the HERC1 mutation by investigation of patient and control fibroblasts under normal and nutrient starving conditions. During catabolic state, mTORC1 activity remained high in patient fibroblasts, which stands in stark contrast to its downregulation in controls. This was corroborated by an abnormally high phosphorylation of S6K1-kinase, a direct downstream target of mTORC1, in patients. Moreover, autophagy, usually enhanced in catabolic states, was down-regulated in patient fibroblasts. These data confirm that the missense variant found in both patients results in a gain-of-function for the mutant HERC1 protein.

The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses.

HERC1 is a ubiquitin ligase protein, which, when mutated, induces several malformations and intellectual disability in humans. The animal model of HERC1 mutation is the mouse tambaleante characterized by: (1) overproduction of the protein; (2) cerebellar Purkinje cells death by autophagy; (3) dysregulation of autophagy in spinal cord motor neurons, and CA3 and neocortical pyramidal neurons; (4) impairment of associative learning, linked to altered spinogenesis and absence of LTP in the lateral amygdala; and, (5) motor impairment due to delayed action potential transmission, decrease synaptic transmission efficiency and altered myelination in the peripheral nervous system. To investigate the putative role of HERC1 in the presynaptic dynamics we have performed a series of experiments in cultured tambaleante hippocampal neurons by using transmission electron microscopy, FM1-43 destaining and immunocytochemistry. Our results show: (1) a decrease in the number of synaptic vesicles; (2) reduced active zones; (3) less clathrin immunoreactivity and less presynaptic endings over the hippocampal main dendritic trees; which contrast with (4) a greater number of endosomes and autophagosomes in the presynaptic endings of the tambaleante neurons relative to control ones. Altogether these results show an important role of HERC1 in the regulation of presynaptic membrane dynamics.

HERC Ubiquitin Ligases in Cancer.

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3-HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies.

Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions.

We report the in vivo regulation of Inosine-5´-monophosphate dehydrogenase 1 (IMPDH1) in the retina. IMPDH1 catalyzes the rate-limiting step in the de novo synthesis of guanine nucleotides, impacting the cellular pools of GMP, GDP and GTP. Guanine nucleotide homeostasis is central to photoreceptor cells, where cGMP is the signal transducing molecule in the light response. Mutations in IMPDH1 lead to inherited blindness. We unveil a light-dependent phosphorylation of retinal IMPDH1 at Thr159/Ser160 in the Bateman domain that desensitizes the enzyme to allosteric inhibition by GDP/GTP. When exposed to bright light, living mice increase the rate of GTP and ATP synthesis in their retinas; concomitant with IMPDH1 aggregate formation at the outer segment layer. Inhibiting IMPDH activity in living mice delays rod mass recovery. We unveil a novel mechanism of regulation of IMPDH1 in vivo, important for understanding GTP homeostasis in the retina and the pathogenesis of adRP10 IMPDH1 mutations.