ER chaperones in neurodegenerative disease: Folding and beyond

García-Huerta, Paula; Bargsted, Leslie; Rivas, Alexis; Matus, Soledad; Vidal, René L.

doi:10.1016/j.brainres.2016.04.070

Cited by 12 publications

(12 citation statements)

References 109 publications

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“…Genes that encoded enzymes with antioxidant properties, such as the thioredoxin reductase Trxr-1 , and antioxidant genes involved in glutamate metabolism, such as GlnRS , isoQC and QC , were also upregulated with age [ 47 – 50 ]. We also observed increased age-associated expression of chaperone genes ( Cct1 , Cct4 , Cct5 , Cct6 , Hsc70-4 ) and the unfolded protein response transcription factor Xbp1 , consistent with an induction of the unfolded protein response [ 51 – 53 ]. Under stress conditions, there is a translational switch that favors production of stress-related proteins while decreasing translation of other proteins [ 54 ].…”

Section: Resultsmentioning

confidence: 84%

Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence

et al. 2017

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BackgroundAging is associated with functional decline of neurons and increased incidence of both neurodegenerative and ocular disease. Photoreceptor neurons in Drosophila melanogaster provide a powerful model for studying the molecular changes involved in functional senescence of neurons since decreased visual behavior precedes retinal degeneration. Here, we sought to identify gene expression changes and the genomic features of differentially regulated genes in photoreceptors that contribute to visual senescence.ResultsTo identify gene expression changes that could lead to visual senescence, we characterized the aging transcriptome of Drosophila sensory neurons highly enriched for photoreceptors. We profiled the nuclear transcriptome of genetically-labeled photoreceptors over a 40 day time course and identified increased expression of genes involved in stress and DNA damage response, and decreased expression of genes required for neuronal function. We further show that combinations of promoter motifs robustly identify age-regulated genes, suggesting that transcription factors are important in driving expression changes in aging photoreceptors. However, long, highly expressed and heavily spliced genes are also more likely to be downregulated with age, indicating that other mechanisms could contribute to expression changes at these genes. Lastly, we identify that circular RNAs (circRNAs) strongly increase during aging in photoreceptors.ConclusionsOverall, we identified changes in gene expression in aging Drosophila photoreceptors that could account for visual senescence. Further, we show that genomic features predict these age-related changes, suggesting potential mechanisms that could be targeted to slow the rate of age-associated visual decline.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4304-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 84%

Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence

et al. 2017

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“…Protein homeostasis involves the regulation of protein formation (synthesis, folding, oligomerization), protein degradation, and peptide recycling (turnover) 1 . Protein turnover is controlled through two major pathways: the autophagosome-lysosomal system and the ubiquitin proteasome system (UPS) 2 , the latter tasked with identifying misfolded and foreign proteins.…”

Section: Introductionmentioning

confidence: 99%

Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia

Bousman

Luza

Mancuso

et al. 2019

Sci Rep

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Dysregulation of the ubiquitin proteasome system (UPS) has been linked to schizophrenia but it is not clear if this dysregulation is detectable in both brain and blood. We examined free mono-ubiquitin, ubiquitinated proteins, catalytic ubiquitination, and proteasome activities in frozen postmortem OFC tissue from 76 (38 schizophrenia, 38 control) matched individuals, as well as erythrocytes from 181 living participants, who comprised 30 individuals with recent onset schizophrenia (mean illness duration = 1 year), 63 individuals with ‘treatment-resistant’ schizophrenia (mean illness duration = 17 years), and 88 age-matched participants without major psychiatric illness. Ubiquitinated protein levels were elevated in postmortem OFC in schizophrenia compared to controls (p = <0.001, AUC = 74.2%). Similarly, individuals with ‘treatment-resistant’ schizophrenia had higher levels of ubiquitinated proteins in erythrocytes compared to those with recent onset schizophrenia (p < 0.001, AUC = 65.5%) and controls (p < 0.001, AUC = 69.4%). The results could not be better explained by changes in proteasome activity, demographic, medication, or tissue factors. Our results suggest that ubiquitinated protein formation may be abnormal in both the brain and erythrocytes of those with schizophrenia, particularly in the later stages or specific sub-groups of the illness. A derangement in protein ubiquitination may be linked to pathogenesis or neurotoxicity in schizophrenia, and its manifestation in the blood may have prognostic utility.

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“…HSPA5, PDIA3, PDIA4, PDIA6, and DNAJC3) that are commonly engaged in presence of misfolded proteins (Bartels et al, 2019; Kim et al, 2020; Montibeller and de Belleroche, 2018; Synofzik et al, 2014; Wang et al, 2016). This elevation of ER stress modulators can be indicative of neurodegenerative states, in which the unfolded protein response (UPR) is activated to resolve misfolded species (Garcia-Huerta et al, 2016; Hetz and Saxena, 2017). These data demonstrate that loss of WASH function not only alters endo-lysosomal trafficking, but also causes increased stress on cellular homeostasis.…”

Section: Resultsmentioning

confidence: 99%

Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans

Courtland

Bradshaw

Waitt

et al. 2020

Preprint

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Mutation of the WASH complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4c.3056C>G mutation. Quantitative spatial proteomics analysis of SWIPP1019R mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIPP1019R results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not only impacts cognition, but also causes significant progressive motor deficits in mice. Remarkably, a retrospective analysis of SWIPP1019R patients confirms motor deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.

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ER chaperones in neurodegenerative disease: Folding and beyond

Cited by 12 publications

References 109 publications

Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence

Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence

Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia

Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans

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