Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson’s disease

Dick, Fiona; Tysnes, Ole‐Bjørn; Alves, Guido; Nido, Gonzalo S.; Tzoulis, Charalampos

doi:10.1016/j.isci.2023.105925

Cited by 7 publications

(3 citation statements)

References 54 publications

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“…Finally, we performed Ribo-Seq to directly assess the contribution of mRNA translation to proteome alterations and to quantify ribosome stalling and pausing in the aging vertebrate brain. Our analyses provide a compelling hypothesis to explain the lack of correspondence between transcriptome and proteome changes, an evolutionary conserved (Janssens et al 2015;Wei et al 2015;Walther et al 2015;David et al 2010;Takemon et al 2021;Gerdes Gyuricza et al 2022;Kelmer Sacramento et al 2020), yet understudied aspect of age-related proteostasis impairment that has been linked to neurodegeneration in humans (Dick et al 2023). We demonstrate that agedependent translation dysfunction, leading to aberrant elongation pausing and increased aggregation can account for age-related alterations of the proteome independently of changes in mRNA levels.…”

Section: Introductionmentioning

confidence: 80%

“…Such alterations lead to the depletion of protein complexes involved in DNA/RNA-binding and protein synthesis, and remodel the proteomes of organelles such as mitochondria. This altered translation dynamic also provides a mechanistic explanation for the highly conserved age-related discrepancies between transcriptome and proteome changes ( 9 , 10 , 11 , 12 , 13 , 14 , 6 ), which have been linked to neurodegeneration in humans ( 15 ). Thus, our work reveals how the biogenesis of a specific subset of proteins might further enhance vulnerabilities of the proteostasis system in the aging brain and contribute to the exacerbation of other aging hallmarks.…”

Section: Main Textmentioning

confidence: 99%

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Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Di Fraia,

Marino,

Lee

et al. 2023

Preprint

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Protein homeostasis declines both in aging and neurodegenerative diseases, yet our understanding of how aging affects brain proteostasis is still limited. Here, we measured and integrated the effects of aging on the transcriptome, translatome, and multiple layers of the proteome in the brain of a short-lived killifish. We found that aging causes a decoupling between transcript and protein levels leading to, e.g., decreased abundance of proteins enriched in basic amino acids independent of mRNA changes. Chronic proteasome impairment in vivo induces aging signatures in lysosomes and mitochondria. However, it does not recapitulate the age-related decoupling between transcripts and proteins. Instead, increased translation pausing and reduced ribosome levels reprogram protein synthesis independently of transcription. These changes in protein biogenesis likely reduce the availability of key protein complexes and contribute to the remodeling of organelles in older brains.

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Section: Introductionmentioning

confidence: 80%

Section: Main Textmentioning

confidence: 99%

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Di Fraia,

Marino,

Lee

et al. 2023

Preprint

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“…Therefore, specific, sensitive, either central or peripheral biomarkers are strongly needed, especially for the early diagnosis and severity of PD, differential diagnosis from similar pathologies and for monitoring curative therapies. Omics studies, as metabolomics and proteomics, promise advances in the investigation of molecular mechanisms of the NDs as well as on the biomarker discovery [4,[10][11][12][13][14][15][16]. Although in lower number than proteomic researches in AD, extensive proteomic studies in PD are in progress, and performed on CSF, plasma/serum, urine, tears, saliva and tissue samples from brain-banks [4,[10][11][12].…”

Section: Introductionmentioning

confidence: 99%

A top‐down proteomic approach reveals a salivary protein profile able to classify Parkinson's disease with respect to Alzheimer's disease patients and to healthy controls

et al. 2023

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Parkinson's disease (PD) is a complex neurodegenerative disease with motor and non‐motor symptoms. Diagnosis is complicated by lack of reliable biomarkers. To individuate peptides and/or proteins with diagnostic potential for early diagnosis, severity and discrimination from similar pathologies, the salivary proteome in 36 PD patients was investigated in comparison with 36 healthy controls (HC) and 35 Alzheimer's disease (AD) patients. A top‐down platform based on HPLC‐ESI‐IT‐MS allowed characterizing and quantifying intact peptides, small proteins and their PTMs (overall 51). The three groups showed significantly different protein profiles, PD showed the highest levels of cystatin SA and antileukoproteinase and the lowest of cystatin SN and some statherin proteoforms. HC exhibited the lowest abundance of thymosin β4, short S100A9, cystatin A, and dimeric cystatin B. AD patients showed the highest abundance of α‐defensins and short oxidized S100A9. Moreover, different proteoforms of the same protein, as S‐cysteinylated and S‐glutathionylated cystatin B, showed opposite trends in the two pathological groups. Statherin, cystatins SA and SN classified accurately PD from HC and AD subjects. α‐defensins, histatin 1, oxidized S100A9, and P‐B fragments were the best classifying factors between PD and AD patients. Interestingly statherin and thymosin β4 correlated with defective olfactory functions in PD patients. All these outcomes highlighted implications of specific proteoforms involved in the innate‐immune response and inflammation regulation at oral and systemic level, suggesting a possible panel of molecular and clinical markers suitable to recognize subjects affected by PD.

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Brain Proteome Profiling Reveals Common and Divergent Signatures in Parkinson’s Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy

Dick,

Johanson,

Tysnes

et al. 2024

Mol Neurobiol

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The molecular pathogenesis of degenerative parkinsonisms, including Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and Multiple system atrophy (MSA), remains largely unknown. To gain novel insight into molecular processes associated with these diseases, we conducted a proteome-wide expression study in prefrontal cortex tissue from a cohort of 181 individuals, comprising PD (N = 73), PSP (N = 18), MSA (N = 17) and healthy control (N = 73). Using marker gene profiles, we first assess the cellular composition of the samples and, subsequently, identify distinct protein signatures for each disease, while correcting for cell composition. Our findings indicate that all three diseases are characterized by a structural and/or functional loss of deep cortical neurons, while PD exhibits an additional decrease in somatostatin-expressing interneurons, as well as in endothelial cells. Differential protein expression analysis identified multiple proteins and pathways with disease-specific expression, some of which have previously been associated with parkinsonism or neurodegeneration in general. Notably, we observed a strong mitochondrial signature which was present in both PD and PSP, albeit of a different composition and most pronounced in PSP, but not in MSA where immunological/inflammation-related pathways dominated. Additionally, we identified protein signatures associated with the severity of α-synuclein pathology in PD and showed that these are highly enriched in an upregulation of mitochondrial processes, specifically related to oxidative phosphorylation and in particular respiratory complexes I and IV. We identify multiple novel signatures of protein expression, associated with PD, PSP, and MSA, as well as with the severity of α-synuclein pathology in the PD brain.

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Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson’s disease

Cited by 7 publications

References 54 publications

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

A top‐down proteomic approach reveals a salivary protein profile able to classify Parkinson's disease with respect to Alzheimer's disease patients and to healthy controls

Brain Proteome Profiling Reveals Common and Divergent Signatures in Parkinson’s Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy

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