Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells

Abstract

Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

“…Interestingly, we also detected a downregulation in different HSPs transcripts and protein levels in the lungs of bleomycin-injured mice and in our in vitro model, including a greater than 2-fold decrease in levels for Hsp70, Hsp90, and Hsp40. Importantly, these findings support the current paradigm in the aging field that proteostasis collapse contribute to cellular senescence [22-24].…”

“…Although induction of cellular senescence has been attributed to a variety of factors, such as telomere attrition or mitochondrial dysfunction [20, 21], decline in the proteostasis network (PN) has recently emerged as an important causal factor [22-24]. The PN is a nexus of pathways that act in concert to maintain the integrity of the proteome.…”

Pathogenic or protective? Neuropeptide Y in amyotrophic lateral sclerosis

“…NPY‐induced autophagy has also been reported in cortical neurons through the activation of Y1, Y2 and Y5 receptors (Ferreira‐Marques et al., 2016). Antagonists specific for these receptors were each able to inhibit NPY’s stimulation of autophagy (Ferreira‐Marques et al., 2016), with autophagy likely enhanced through inhibition of mTOR activity (Aveleira et al., 2020). The induction of autophagy has been proposed as a therapeutic strategy to enhance neuronal survival in ALS (Barmada et al., 2014; Madeo, Eisenberg, & Kroemer, 2009), and inhibition of mTOR pathways to enhance autophagy is currently the focus of a phase II clinical trial in ALS patients (Mandrioli et al., 2018).…”

Central and Peripheral NPY Age-Related Regulation: A Comparative Analysis in Fish Translational Models

“…Further, it has recently been demonstrated that NPY delays the cellular aging phenotype associated to Hutchinson-Gilford Progeria Syndrome (HGPS), paving the way for the hypothesis that this neuropeptide may be exploited to block the premature onset of aging hallmarks in patients affected by HGPS by stimulating autophagy and decreasing progerin accumulation, rescuing nuclear abnormalities, and delaying cellular senescence [ 39 ]. In particular, the authors reported interesting findings displaying the NPY-induced enhancement of autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from patients affected by HGPS.…”

“…In particular, the authors reported interesting findings displaying the NPY-induced enhancement of autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from patients affected by HGPS. In more detail, they showed that NPY preserves nuclear morphology and reduces the number of dysmorphic nuclei [ 39 ].…”