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- Neurological
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
The Role of ATP Citrate Lyase in Myelin Formation and Maintenance
Schneider et al., Glia. 2024.
https://pubmed.ncbi.nlm.nih.gov/39318247/
Myelin formation by Schwann cells is critical for peripheral nervous system development and long-term neuronal function. The study examined how acetyl coenzyme A (acetyl-CoA), essential for lipid synthesis in myelin, is derived, with a focus on mitochondrial ATP citrate lysate (ACLY). By using both sexes in a Schwann cell–specific ACLY knockout mouse model, the authors reported that ACLY plays a role in acetyl-CoA supply for myelin maintenance but not myelin formation. ACLY is necessary for sustaining myelin gene expression and preventing nerve injury pathways. This work highlights a unique dependency on mitochondrial acetyl-CoA for Schwann cell integrity, providing insights into lipid metabolism in neuronal repair. Supported by ORIP (T35OD011078), NICHD, and NINDS.
Cdk8/CDK19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation and Can Phenotypically Suppress Pink1 Deficiency in Drosophila
Liao et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-47623-8
Pink1 is a mitochondrial kinase implicated in Parkinson’s disease and is conserved among humans, rodents, and flies. In this study, researchers found that Cdk8 in Drosophila (i.e., the orthologue of vertebrate CDK8 and CDK19) promotes the phosphorylation of Drp1 (i.e., a protein required for mitochondrial fission) at the same residue as Pink1. Cdk8 is expressed in both the cytoplasm and nucleus, and neuronal loss of Cdk8 reduces fly life span and causes bang sensitivity and elongated mitochondria in both muscles and neurons. Overexpression of Cdk8 suppresses elevated levels of reactive oxygen species, mitochondrial dysmorphology, and behavioral defects in flies with low levels of Pink1. These findings suggest that Cdk8 regulates Drp1-mediated mitochondrial fission in a similar manner as Pink1 and may contribute to the development of Parkinson’s disease. Supported by ORIP (R24OD022005, R24OD031447, P40OD018537, P40OD010949), NICHD, and NINDS.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.
Molecular Basis of Human Trace Amine-Associated Receptor 1 Activation
Zilberg et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-023-44601-4
The authors reported the cryogenic electron microscopy structure of human trace amine-associated receptor 1 (hTAAR1, hTA1) signaling complex, a key modulator in monoaminergic neurotransmission, as well as its similarities and differences with other TAAR members and rodent TA1 receptors. This discovery has elucidated hTA1’s molecular mechanisms underlining the strongly divergent pharmacological properties of human and rodent TA1 and therefore will boost the translation of preclinical studies to clinical applications in treating disorders of dopaminergic dysfunction, metabolic disorders, cognitive impairment, and sleep-related dysfunction. Supported by ORIP (S10OD019994, S10OD026880, and S10OD030463), NIDA, NIGMS, NIMH, and NCATS.
Very-Long-Chain Fatty Acids Induce Glial-Derived Sphingosine-1-Phosphate Synthesis, Secretion, and Neuroinflammation
Chung et al., Cell Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37084732/
Very-long-chain fatty acids (VLCFAs) are the most abundant fatty acids in myelin. During age‑associated degeneration of myelin, glia are exposed to increased levels of VLCFAs. Investigators previously described a novel phenotype in patients that harbors a novel variant in the peroxisomal enzyme ACOX1. Here, they report that that glial loss of ACOX1 leads to an increase of VLCFAs, which results in a concomitant increase in sphingosine-1-phosphate (S1P). They found that suppressing S1P function attenuates the pathological phenotypes caused by excess VLCFAs. This work suggests that lowering of VLCFAs and S1P could be applied as a treatment avenue for multiple sclerosis. Supported by ORIP (R24OD022005, R24OD031447, P40OD018537), NINDS, and NICHD
Allelic Strengths of Encephalopathy-Associated UBA5 Variants Correlate Between In Vivo and In Vitro Assays
Pan et al., eLife. 2023.
https://pubmed.ncbi.nlm.nih.gov/37502976/
The UBA5 gene is associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder, in humans. The link between UBA5 variants and severity of DEE44, however, is not established. Investigators developed humanized fly models carrying a series of patient UBA5 variants. These flies showed differences in survival rates, developmental progress, life span, and neurological well-being. The severity of these defects correlated strongly with functional defects of UBA5 variants, allowing the classification of UBA5 loss-of-function variants into mild, intermediate, and severe allelic strengths in patients. This study provides resources for systematic investigation of the mechanistic link between UBA5 variants and DEE44 and for developing diagnostic approaches. Supported by ORIP (R24OD022005, R24OD031447, U54OD035865) and NCATS.
A Defect in Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism and Causes Elevated Ceramide Levels
Dutta et al., Nature Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37653044/
Human mitochondrial enoyl coenzyme A reductase (Mecr), required for the last step of mitochondrial fatty acid synthesis (mtFAS), is linked to pediatric-onset neurodegeneration, but with unknown mechanisms. Researchers investigated phenotypes of mecr mutants in Drosophila and human-derived fibroblasts. They found that loss of function of Mecr in the whole body resulted in a defect in Fe-S cluster biogenesis and increased iron levels, leading to elevated ceramide levels and lethality in flies. Similar elevated ceramide levels and impaired iron homeostasis were observed human-derived fibroblasts with Mecr deficiency. Neuronal loss of Mecr led to progressive neurodegeneration in flies. This study pointed out a mechanistic link between mtFAS and neurodegeneration through Mecr. Supported by ORIP (R24OD022005, R24OD031447), NICHD, and NINDS.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography
Coughlan et al., JAMA Neurology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37010830/
To understand the predominance (70%) of women among individuals with Alzheimer’s disease, the investigators studied regional tau and β-amyloid (Aβ) in relation to age at menopause and hormone therapy (HT) in postmenopausal women and age-matched men using positron emission tomography. The study demonstrated that females exhibited higher tau deposition compared with age-matched males, particularly in the setting of elevated Aβ; earlier age at menopause and late initiation of HT were associated with increased tau vulnerability. This study suggests female individuals with these conditions may be at higher risk of pathological burden. Supported by ORIP (S10OD025245), NIA, and NICHD.