Rpt2 proteasome subunit reduction causes Parkinson's disease like symptoms in Drosophila

Fernández-Cruz, Iván; Sánchez-Díaz, Iván; Narváez-Padilla, Verónica; Reynaud, Enrique

doi:10.1016/j.ibror.2020.07.001

Cited by 11 publications

(6 citation statements)

References 73 publications

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“…Knock‐out of the PSMC1 ortholog in mice was shown to be embryonic lethal 30 . Similarly, silencing the Drosophila PSMC1 ortholog, Rpt2 , pan‐neuronally, resulted in larvae not completing pupation 31 . Utilizing a UAS‐Gal4 tissue‐specific knock‐down system, Fernández‐Cruz et al 31 have shown that expressing Rpt2 ‐RNAi under a GMR‐Gal4 driver resulted in eye degeneration with severe depigmentation and necrosis.…”

Section: Resultsmentioning

confidence: 99%

“…PSMC1 conditional knock‐out mice exhibited 26S proteasome depletion and Lewy‐like inclusions, 30 while PSMC1 heterozygous knock‐out mice did not show any effects on the mouse brain (yet their embryonic fibroblasts did show decreasing levels of PSMC1 and cell cycle arrest) 42 . In quest of possible association between PSMC1 and Parkinson diseases, Fernández‐Cruz et al 31 have shown that following Rpt2 knock‐down in the D. melanogaster central nervous system (CNS) under Elav‐Gal4 driver and thermosensitive Gal80, proteasome activity was reduced, and augmentation of insoluble ubiquitinated protein was observed.…”

Section: Discussionmentioning

confidence: 99%

“…30 Similarly, silencing the Drosophila PSMC1 ortholog, Rpt2, pan-neuronally, resulted in larvae not completing pupation. 31 Utilizing a UAS-Gal4 tissue-specific knock-down system, Fernández-Cruz et al 31 have shown that expressing Rpt2-RNAi under a GMR-Gal4 driver resulted in eye degeneration with severe depigmentation and necrosis. We aimed to assess the ability of the wild type and mutant (p.I255T) human PSMC1 to rescue the eye phenotype generated by Rpt2 silencing in Drosophila.…”

Section: In Vivo Drosophila Rescue Experimentsmentioning

confidence: 99%

“…Cruz et al31 have shown that following Rpt2 knock-down in the D. melanogaster central nervous system (CNS) under Elav-Gal4 driver and thermosensitive Gal80, proteasome activity was reduced, and augmentation of insoluble ubiquitinated protein was observed.Notably, previous studies have tested possible association of PSMC1 with human diseases: a clinical report of a heterozygous deletion of varying segments of a 14q32.11 locus with an overlapping deletion of KCNK13, PSMC1, NRDE2, CALM1, TTC7B, and RPS6KA5 was associated with developmental and speech acquisition delays in three unrelated patients. However, one of the patients' mother tested positive for heroin at delivery and had with a history of heroin and tobacco use in previous pregnancies, and the nonaffected mother of another affected individual shared the heterozygous deletion of her affected son.…”

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confidence: 99%

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PSMC1 variant causes a novel neurological syndrome

et al. 2022

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Proteasome 26S, the eukaryotic proteasome, serves as the machinery for cellular protein degradation. It is composed of the 20S core particle and one or two 19S regulatory particles, composed of a base and a lid. To date, several human diseases have been associated with mutations within the 26S proteasome subunits; only one of them affects a base subunit. We now delineate an autosomal recessive syndrome of failure to thrive, severe developmental delay and intellectual disability, spastic tetraplegia with central hypotonia, chorea, hearing loss, micropenis and undescended testes, as well as mild elevation of liver enzymes. None of the affected individuals achieved verbal communication or ambulation. Ventriculomegaly was evident on MRI. Homozygosity mapping combined with exome sequencing revealed a disease‐associated p.I328T PSMC1 variant. Protein modeling demonstrated that the PSMC1 variant is located at the highly conserved putative ATP binding and hydrolysis domain, and is suggested to interrupt a hydrophobic core within the protein. Fruit flies in which we silenced the Drosophila ortholog Rpt2 specifically in the eye exhibited an apparent phenotype that was highly rescued by the human wild‐type PSMC1, yet only partly by the mutant PSMC1, proving the functional effect of the p.I328T disease‐causing variant.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: In Vivo Drosophila Rescue Experimentsmentioning

confidence: 99%

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confidence: 99%

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PSMC1 variant causes a novel neurological syndrome

et al. 2022

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“…αSyn induced significant accumulation of ubiquitinated proteins when Rpt2 was depleted, suggesting proteasome dysfunction. Consistently, depletion of Rpt2 resulted in mice in accumulation of αSyn and development of Lewy Body-like inclusions [ 94 ], and strongly induced neurodegeneration and PD-like symptoms in Drosophila [ 95 ]. Significant alteration in the expression of proteasome subunits was reported in the spinal cord of the A30P αSyn variant in mice [ 96 ].…”

Section: Discussionmentioning

confidence: 97%

α-Synuclein Decreases the Abundance of Proteasome Subunits and Alters Ubiquitin Conjugates in Yeast

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Galka

Häffner

et al. 2021

Cells

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Parkinson’s disease (PD) is the most prevalent movement disorder characterized with loss of dopaminergic neurons in the brain. One of the pathological hallmarks of the disease is accumulation of aggregated α-synuclein (αSyn) in cytoplasmic Lewy body inclusions that indicates significant dysfunction of protein homeostasis in PD. Accumulation is accompanied with highly elevated S129 phosphorylation, suggesting that this posttranslational modification is linked to pathogenicity and altered αSyn inclusion dynamics. To address the role of S129 phosphorylation on protein dynamics further we investigated the wild type and S129A variants using yeast and a tandem fluorescent timer protein reporter approach to monitor protein turnover and stability. Overexpression of both variants leads to inhibited yeast growth. Soluble S129A is more stable and additional Y133F substitution permits αSyn degradation in a phosphorylation-independent manner. Quantitative cellular proteomics revealed significant αSyn-dependent disturbances of the cellular protein homeostasis, which are increased upon S129 phosphorylation. Disturbances are characterized by decreased abundance of the ubiquitin-dependent protein degradation machinery. Biotin proximity labelling revealed that αSyn interacts with the Rpt2 base subunit. Proteasome subunit depletion by reducing the expression of the corresponding genes enhances αSyn toxicity. Our studies demonstrate that turnover of αSyn and depletion of the proteasome pool correlate in a complex relationship between altered proteasome composition and increased αSyn toxicity.

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