Related Experiment Video
Updated: Sep 9, 2025
07:46
Gait Analysis of Age-dependent Motor Impairments in Mice with Neurodegeneration
Published on: June 18, 2018
12.1K
Proteasome mutations associated with CANDLE syndrome cause altered neuronal development by dysregulating polyamine
Clayton W Winkler1, Benjamin Schwarz2, Katie Williams3
1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity (LNII), Rocky Mountain Laboratories (RML), National Institute of Allergy and Infectious Diseases (NIAID), NIH, Hamilton, MT, USA.
Biorxiv : the Preprint Server for Biology
|September 2, 2025
Summary
Genetic mutations causing proteasome dysfunction lead to Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. Researchers found inhibiting Ornithine decarboxylase (ODC) repaired neuronal development in CANDLE cerebral organoids by reducing polyamines.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Proteasome dysfunction is linked to multi-organ diseases like CANDLE syndrome.
- Neurological symptoms in CANDLE syndrome suggest impacts on neuronal development and function.
Purpose of the Study:
- To investigate the impact of proteasome dysfunction on neuronal development using cerebral organoids from CANDLE syndrome patients.
- To identify molecular mechanisms underlying neurological deficits in CANDLE syndrome and explore therapeutic targets.
Main Methods:
- Generated cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) of CANDLE patients and healthy controls.
- Analyzed neuronal development, polyamine levels, and Ornithine decarboxylase (ODC) expression in COs and cerebrospinal fluid (CSF).
- Utilized ODC inhibition as a therapeutic intervention in CANDLE COs.
Main Results:
- CANDLE COs displayed impaired neuronal development compared to controls.
- Elevated polyamine levels were observed in CANDLE COs and patient CSF, correlated with impaired maturation.
- Increased Ornithine decarboxylase (ODC) expression was found in CANDLE neurons.
- ODC inhibition normalized polyamine levels and rescued neuronal maturation in CANDLE COs.
Conclusions:
- Proteasome dysfunction in CANDLE syndrome impairs neuronal development via polyamine overproduction, mediated by ODC dysregulation.
- Targeting ODC offers a potential therapeutic strategy for neurological complications associated with proteasomal dysfunction.
Related Concept Videos
01:13The Proteasome
1.1K
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
1.1K
00:50Anaphase Promoting Complex
2.9K
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
2.9K
01:31Translation
143.3K
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
143.3K
01:19Allosteric Proteins-ATCase
5.9K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.9K
02:23Abnormal Proliferation
4.6K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
01:20Inborn Errors of Metabolism
240
Phenylketonuria (PKU) is a protein metabolism disorder characterized by high blood levels of the amino acid phenylalanine. This results from a mutation in the gene responsible for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up in the blood, leading to symptoms such as vomiting, rashes, seizures, growth deficiency, and severe mental retardation. An early diagnosis and a diet restricting phenylalanine intake...
240