The organization of chromatin is tightly regulated, being crucial for the control of gene expression programs, both during organism development and in tissue homeostasis. In particular, perinuclear heterochromatin has an evolutionarily conserved function in restraining the activity of mobile genetic elements, also known as transposable elements (TEs), which are potentially mutagenic. Aging and several aging-related diseases have been proposed to involve a deregulation of chromatin organisation. A widespread relaxation of heterochromatin, leading to unscheduled TE expression and de novo genomic insertion, associated with accumulation of DNA damage, have recently emerged as key contributors of aging and aging-dependent pathologies, including several neurological disorders, such as Alzheimer’s disease (AD). However, it is unclear how heterochromatin is challenged and its organisation is altered during aging and the pathogenesis of those disorders, including AD. Understanding the underlying molecular mechanisms could lead to the identification of potential biomarkers and therapeutic targets for prevention and treatment of some currently incurable diseases, such as AD, which are expected to become epidemic in the coming decades. In this Thesis, we demonstrate that PIN1, a unique enzyme that isomerises phosphorylated-S/T-P aminoacid motifs, and whose activity promotes healthy aging and protects against AD, has a fundamental function, conserved from Drosophila to humans, in maintaining the formation of heterochromatin, thus preventing toxic hyperactivity of TEs. We further provide evidence that, in Drosophila, the PIN1 ortholog Dodo preserves the mechanical properties and the compartmentalization of the nuclear envelope, thus protecting Heterochromatin protein 1a (HP1a), a major regulator of heterochromatin, from proteasome-dependent degradation. Mechanistically, in both Drosophila and human cells, PIN1 promotes the anchoring of HP1a to the nuclear lamina, in line with data previously obtained in our laboratory suggesting that Dodo interacted with both HP1a and B-type Lamin proteins. Our findings identify a mechanism by which PIN1 safeguards brain neurons from mechanical stress, which has been proposed as an important contributor to AD pathogenesis.

The prolyl-isomerase Pin1 maintains heterochromatin by preserving nuclear envelope structure in brain tissue / Ferrari Bravo, Gloria. - (2019 Oct 30).

The prolyl-isomerase Pin1 maintains heterochromatin by preserving nuclear envelope structure in brain tissue.

Ferrari Bravo, Gloria
2019

Abstract

The organization of chromatin is tightly regulated, being crucial for the control of gene expression programs, both during organism development and in tissue homeostasis. In particular, perinuclear heterochromatin has an evolutionarily conserved function in restraining the activity of mobile genetic elements, also known as transposable elements (TEs), which are potentially mutagenic. Aging and several aging-related diseases have been proposed to involve a deregulation of chromatin organisation. A widespread relaxation of heterochromatin, leading to unscheduled TE expression and de novo genomic insertion, associated with accumulation of DNA damage, have recently emerged as key contributors of aging and aging-dependent pathologies, including several neurological disorders, such as Alzheimer’s disease (AD). However, it is unclear how heterochromatin is challenged and its organisation is altered during aging and the pathogenesis of those disorders, including AD. Understanding the underlying molecular mechanisms could lead to the identification of potential biomarkers and therapeutic targets for prevention and treatment of some currently incurable diseases, such as AD, which are expected to become epidemic in the coming decades. In this Thesis, we demonstrate that PIN1, a unique enzyme that isomerises phosphorylated-S/T-P aminoacid motifs, and whose activity promotes healthy aging and protects against AD, has a fundamental function, conserved from Drosophila to humans, in maintaining the formation of heterochromatin, thus preventing toxic hyperactivity of TEs. We further provide evidence that, in Drosophila, the PIN1 ortholog Dodo preserves the mechanical properties and the compartmentalization of the nuclear envelope, thus protecting Heterochromatin protein 1a (HP1a), a major regulator of heterochromatin, from proteasome-dependent degradation. Mechanistically, in both Drosophila and human cells, PIN1 promotes the anchoring of HP1a to the nuclear lamina, in line with data previously obtained in our laboratory suggesting that Dodo interacted with both HP1a and B-type Lamin proteins. Our findings identify a mechanism by which PIN1 safeguards brain neurons from mechanical stress, which has been proposed as an important contributor to AD pathogenesis.
Mantovani, Fiamma
Del Sal, Giannino; Napoletano, Francesco
Ferrari Bravo, Gloria
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/104554
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