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PYCR1 Levels Track with Premature and Chronological Skin Aging

Kortessa Sotiropoulou, Saniye Yumlu, Tomoko Hirano, Michael Maier, Abigail Loh, Peh Fern Ong, Onn Siong Yim, Chunping Liu, Emmanuel Vial, Umut Altunoğlu, Sheela Nampoothiri, Deepthi de Silva, Björn Fischer-Zirnsak, Hülya Kayserili, Poh San Lai, Oliver Dreesen, Kenji Kabashima, Uwe Kornak, Nathalie Escande-Beillard, Bruno Reversade

Posted on: 17 August 2023 , updated on: 18 August 2023

Preprint posted on 28 May 2023

Eternal youth: Unravelling PYCR1 levels in aging dermal tissues.

Selected by Preethi Krishnaraj

Introduction to PYCR and de Barsy syndrome (OMIM: 614438, 219150 and 616603)

The PYCR1 gene codes for pyrroline-5-carboxylate reductases. This enzyme is found in the mitochondria and plays a crucial role in catalysing the final step in proline biogenesis pathway. PYCR2 and PYCRL are two paralogs of PYCR1.

Mutations in PYCR1 leads to a pre-mature aging condition or cutis laxa known as de Barsy syndrome. It is characterised by wrinkly skin, connective tissue disorders and a range of different syndromes including intrauterine growth retardation, facial dysmorphism, dysplasia of the hips, and delayed motor and cognitive development. Given the function of PYCR1, it has been surprising that many studies observed unaffected proline levels in the serum and primary fibroblasts of PYCR1-deficient patients, thereby arguing against proline auxotrophy.

This study presents five patients with mutations in PYCR1. As part of the study, the authors generated a knock-out mouse model to mimic human de Barsy syndrome, however they observed potential compensatory mechanisms in mice, which might not exist in humans, involving PYCR1 and PYCR2. Furthermore, the authors investigated the dynamics of PYCR1 expression across various age groups in healthy individuals.

PYCR1: A tale of resilience in mice and humans – Exploring its impact on dermal integrity

The authors generated Pycr1-/- mice, which completely lacked PYCR1 protein expression. These mice were viable, fertile, and had a lifespan comparable to their wild-type counterparts. Although the epidermis of these mice remained unaffected, the dermal layer lacked collagen, leading to the thinning of the dermis. However, the overall phenotype in the mouse was still less severe than in humans. Hence, the authors examined the levels of PYCR2, in the fibroblasts of the mouse and observed no significant changes compared to the wild type. In contrast, fibroblasts obtained from patients showed reduced PYCR2 levels. Thus, the authors highlight the importance of PYCR1 in maintaining skin integrity in humans. Furthermore, the authors speculate that a double knockout of Pycr1 and Pycr2 may fully recapitulate de Barsy syndrome in mice, as observed in humans.

PYCR1’s tale in aging and senescence

To investigate whether endogenous PYCR1 correlates with aging, the authors studied proline metabolism under two cellular senescence conditions: (i) stress-induced senescence (ii) chronological telomere erosion, a contributor to natural aging. The authors observed no changes in the RNA levels of PYCR1 and PYCR2 during senescence. However, they did observe a significant reduction in the protein levels, confirming the link between senescence and decreased PYCR1 levels.

Tracing PYCR1 expression through dermal aging

To further validate their findings, the authors examined PYCR1 levels in fibroblasts obtained from a diverse group of healthy individuals aged 15 to 80 years. The younger individuals were aged 15 to 30, while the older individuals were aged 65 to 80. Through immunohistochemistry analyses, the authors confirmed a significant reduction in PYCR1 levels in the dermis of the older individuals compared to the younger ones. This supports the notion that PYCR1 may play a role in the aging process of human dermal tissues.

Summary

In this study, the authors have corroborated that the absence of PYCR1 from birth results in premature aging, while in healthy individuals PYCR1 levels within the dermal lineage naturally decrease with age (Figure 1).

Figure 1: Schematic summary of this study showing the correlation of PYCR1 and the dermal layer. (Adapted from this preprint).

Questions to the authors

  1. What is your take on the possible mechanism behind the unaffected proline levels despite reduced PYCR2 levels in patients carrying mutations in PYCR1?
  2. Could PYCR1 potentially serve as a widespread biomarker for aging-related diseases?

Further reading

  1. Reversade, B. et al. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat. Genet. 41, 1016–1021 (2009).
  2. Zampatti, S. et al. De Barsy Syndrome: A genetically heterogeneous autosomal recessive cutis laxa syndrome related to P5CS and PYCR1 dysfunction. Am. J. Med. Genet. Part A 158A, 927–931 (2012).

Tags: aging, cutis laxa, de barsy syndrome

doi: https://doi.org/10.1242/prelights.35408

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