PYCR1
Pyrroline-5-carboxylate reductase 1, mitochondrial (EC 1.5.1.2) (P5C reductase 1) (P5CR 1)
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Aging is a complex biological process. A study of pyrroline-5-carboxylate reductase 1 (PYCR1) deficiency, which causes a progeroid syndrome, may not only shed light on its genetic contribution to autosomal recessive cutis laxa (ARCL) but also help elucidate the functional mechanisms associated with aging. In this study, we used RNA-Seq technology to examine gene expression changes in primary skin fibroblasts from healthy controls and patients with [i]PYCR1[/i] mutations. Approximately 22 and 32 candidate genes were found to be up- and downregulated, respectively, in fibroblasts from patients. Among the downregulated candidates in fibroblasts with [i]PYCR1[/i] mutations, a strong reduction in the expression of 17 genes (53.1%) which protein products are localized in the extracellular space was detected. These proteins included several important ECM components, periostin (POSTN), elastin (ELN), and decorin (DCN); genetic mutations in these proteins are associated with different phenotypes of aging, such as cutis laxa and joint and dermal manifestations. The differential expression of ten selected extracellular space genes was further validated using quantitative RT-PCR. Ingenuity Pathway Analysis revealed that some of the affected genes may be associated with cardiovascular system development and function, dermatological diseases and conditions, and cardiovascular disease. [i]POSTN[/i], one of the most downregulated gene candidates in affected individuals, is a matricellular protein with pivotal functions in heart valvulogenesis, skin wound healing, and brain development. Perturbation of PYCR1 expression revealed that it is positively correlated with the POSTN levels. Taken together, POSTN might be one of the key molecules that deserves further investigation for its role in this progeroid neurocutaneous syndrome.
Keywords
- ARCL2B
- Aging
- PYCR1
- cutis laxa
- periostin
- progeroid
Most human neurodegenerative diseases are sporadic and appear later in life. Aging and neurodegeneration are closely associated, and recent investigations reveal that endoplasmic reticulum (ER) stress is involved in the progression of these features. Immunoglobulin heavy chain-binding protein (BiP) is an ER chaperone that is central to ER functions. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence to elucidate the effect of a functional defect in an ER chaperone in multicellular organisms. The homozygous mutant BiP mice died within several hours after birth because of respiratory failure with an impaired biosynthesis of pulmonary surfactant by alveolar type II cells. The heterozygous mutant BiP mice grew up to be apparently normal adults, although some of them revealed motor disabilities as they aged. Here, we report that the synthesis of a mitochondrial protein, pyrroline-5-carboxylate reductase 1 (PYCR1), is enhanced in the brains of homozygous mutant BiP mice. We performed a two-dimensional gel analysis followed by liquid chromatography-tandem mass spectrometry. PYCR1 was identified as one of the enhanced proteins. We also found that sublethal ER stress caused by tunicamycin treatment induced the synthesis of PYCR1 in murine fibroblasts. PYCR1 has been shown to be related to the aging process. Mutations in the PYCR1 gene cause cutis laxa with progeroid features and mental retardation. These findings suggest a pathophysiological interaction between ER stress and a mitochondrial function in aging.
MeSH Terms
- Activating Transcription Factor 6
- Animals
- Cell Line
- Electrophoresis, Gel, Two-Dimensional
- Endoplasmic Reticulum Stress
- Gene Knock-In Techniques
- Heat-Shock Proteins
- Homozygote
- Membrane Proteins
- Mice
- Microscopy, Fluorescence
- Mutagenesis
- Protein-Serine-Threonine Kinases
- Pyrroline Carboxylate Reductases
- RNA Interference
- RNA, Messenger
- RNA, Small Interfering
- Tandem Mass Spectrometry
- Tunicamycin
- eIF-2 Kinase
Keywords
- Aging
- Chaperone
- ER stress
- Mitochondria
- UPR