RESUMO
Pyruvate dehydrogenase (PDH) deficiency is caused by a number of pathogenic variants and the most common are found in the PDHA1 gene. The PDHA1 gene encodes one of the subunits of the PDH enzyme found in a carbohydrate metabolism pathway involved in energy production. Pathogenic variants of PDHA1 gene usually impact the α-subunit of PDH causing energy reduction. It potentially leads to increased mortality in sufferers. Potential treatments for this disease include dichloroacetate and phenylbutyrate, previously used for other diseases such as cancer and maple syrup urine disease. However, not much is known about their efficacy in treating PDH deficiency. Effective treatment for PDH deficiency is crucial as carbohydrate is needed in a healthy diet and rice is the staple food for a large portion of the Asian population. This review analysed the efficacy of dichloroacetate and phenylbutyrate as potential treatments for PDH deficiency caused by PDHA1 pathogenic variants. Based on the findings of this review, dichloroacetate will have an effect on most PDHA1 pathogenic variant and can act as a temporary treatment to reduce the lactic acidosis, a common symptom of PDH deficiency. Phenylbutyrate can only be used on patients with certain pathogenic variants (p.P221L, p.R234G, p.G249R, p.R349C, p.R349H) on the PDH protein. It is hoped that the review would provide an insight into these treatments and improve the quality of lives for patients with PDH deficiency.
Assuntos
Doença da Deficiência do Complexo de Piruvato Desidrogenase , Humanos , Fenilbutiratos/uso terapêutico , Piruvato Desidrogenase (Lipoamida)/genética , Piruvato Desidrogenase (Lipoamida)/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/tratamento farmacológico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genéticaRESUMO
Additional complexity in the post-translational modification of proteins by ubiquitin is achieved by ubiquitin phosphorylation, for example within PINK1-parkin mediated mitophagy. We performed a preliminary proteomic analysis to identify proteins differentially modified by ubiquitin in HEK293T, compared to phosphomimetic ubiquitin (Ser65Asp), and identified small ubiquitin-related modifier 2 (SUMO2) as a candidate. By transfecting SUMO2 and its C-terminal-GG deletion mutant, along with phosphomimetic ubiquitin, we confirm that ubiquitin modifies SUMO2, rather than vice versa. Further investigations revealed that transfected SUMO2 can also be conjugated by endogenous phospho-Ser65-(poly)ubiquitin in HEK293T cells, pointing to a previously unappreciated level of complexity in SUMO2 modification, and that unanchored (substrate-free) polyubiquitin chains may also be subject to phosphorylation.
Assuntos
Proteômica , Ubiquitina , Células HEK293 , Humanos , Fosforilação , Poliubiquitina , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Ubiquitina/metabolismoRESUMO
The metabotropic glutamate receptors (mGluRs) fine-tune the efficacy of synaptic transmission. This unique feature makes mGluRs potential targets for the treatment of various CNS disorders. There is ample evidence to show that the ubiquitin proteasome system mediates changes in synaptic strength leading to multiple forms of synaptic plasticity. The present study describes a novel interaction between post-synaptic adaptors, long Homer-3 proteins, and one of the 26S proteasome regulatory subunits, the S8 ATPase, that influences the degradation of the metabotropic glutamate receptor 1α (mGluR1α). We have shown that the two human long Homer-3 proteins specifically interact with human proteasomal S8 ATPase. We identified that mGluR1α and long Homer-3s immunoprecipitate with the 26S proteasome both in vitro and in vivo. We further found that the mGluR1α receptor can be ubiquitinated and degraded by the 26S proteasome and that Homer-3A facilitates this process. Furthermore, the siRNA mediated silencing of Homer-3 led to increased levels of total and plasma membrane-associated mGluR1α receptors. These results suggest that long Homer-3 proteins control the degradation of mGluR1α receptors by shuttling ubiquitinated mGluR-1α receptors to the 26S proteasome via the S8 ATPase which may modulate synaptic transmission.
Assuntos
Proteínas de Transporte/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais/fisiologia , ATPases Associadas a Diversas Atividades Celulares , Animais , Caderinas/metabolismo , Calnexina/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Córtex Cerebral/citologia , Embrião de Mamíferos , Hipocampo/citologia , Proteínas de Arcabouço Homer , Humanos , Neurônios/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/genética , Transfecção , Ubiquitinação/fisiologiaRESUMO
Hepatocellular carcinoma is one of the largest causes of cancer-related deaths worldwide for which there are very limited treatment options that are currently effective. The ubiquitin-proteasome system has rapidly become acknowledged as both critical for normal cellular function and a frequent target of de-regulation leading to disease. This review appraises the evidence linking the ubiquitin-proteasome system with this devastatingly intractable cancer and asks whether it may prove to be fertile ground for the development of novel therapeutic interventions against hepatocellular carcinoma.
