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DJ-1 depletion prevents immunoaging in T-cell compartments

ABSTRACT: Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7/DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T-cell compartments of both human and mice. Compared with two gender-matched unaffected siblings of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled non-senescent T cells. The observation was further consolidated by the results in 45-week-old DJ-1 knockout mice. Our data demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Mechanistically, DJ-1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T-cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE173904 | GEO | 2022/01/17

REPOSITORIES: GEO

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Human CD8 T cell transcriptomic analysis from the three male siblings of similar ages with DJ-1 loss-of-function or heterozygous mutations

Project description:Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7/DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T-cell compartments of both human and mice. Compared with two gender-matched unaffected siblings of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled non-senescent T cells. The observation was further consolidated by the results in 45-week-old DJ-1 knockout mice. Our data demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Mechanistically, DJ-1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T-cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases.

2022-01-17 | GSE173903 | GEO

PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis during ageing

Project description:Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4+ regulatory T cells (Treg cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs Treg survival starting in young mice and reduces Treg homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible Treg cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As Treg homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish Treg homeostasis.

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Parkinson's disease-associated DJ-1 is required for the expression of GDNF receptor Ret in human neuroblastoma cells

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2010-04-16 | GSE17204 | GEO

RNA binding activity of the recessive parkinsonism protein DJ-1

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2008-03-14 | GSE8632 | GEO

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A chemical probe to monitor parkinsonism-associated protein DJ-1 in live cells

Project description:Oxidative stress is a contingent trigger of Parkinson`s disease (PD). DJ-1, a protein involved in oxidative stress sensing, gained major attention when mutations in its gene were identified in PD patients. Although the study of the corresponding protein function is still in its infancy, a crucial oxidation sensor at a conserved cysteine was linked to the disease. Inspired by inhibition studies with a bacterial homolog of DJ-1 we here screen several amino-epoxycylcohexenones and identify a chemical probe that exhibits specificity for the human protein in various cell lines. The probe selectively labeled the oxidation sensor via nucleophilic attack of the conserved cysteine onto the epoxide ring. This covalent addition occurred only in the reduced state. Whole proteome studies in HeLa, A549 and SHSY5Y cell lines confirmed strong enrichment of solely reduced DJ-1 which was diminished by increasing oxidative stress. The probe thus facilitates the first selective in situ monitoring of DJ-1 in its reduced state and enables studying the function of this important biomarker in dependence of oxidative stress.

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DJ-1 depletion prevents immunoaging in T-cell compartments

Project description:DJ-1 depletion prevents immunoaging in T-cell compartments

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