Related Experiment Video

Updated: Jul 6, 2026

Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
14:32

Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates

Published on: February 27, 2016

Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1

Hélène Catoire1, Matthieu Y Pasco, Aida Abu-Baker

  • 1INSERM, Laboratory of Neuronal Cell Biology and Pathology, Center for Psychiatry and Neuroscience UMR 894, University of Paris Descartes, Equipe d'accueil 4059, 75014 Paris, France.

Human Molecular Genetics
|April 10, 2008
PubMed

Insights

In oculopharyngeal muscular dystrophy (OPMD), inhibiting sirtuin (Sir2) and AMP-activated protein kinase (AMPK) protects muscle cells. This finding offers new therapeutic strategies for polyalanine diseases.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by polyalanine expansion in the PABPN1 protein, leading to muscle degeneration.
  • Sirtuins and AMP-activated protein kinase (AMPK) are known modulators of cellular metabolism and longevity, and are potential therapeutic targets for degenerative diseases.
  • The specific modifiers of mutant PABPN1 toxicity in OPMD remain largely unknown.

Purpose of the Study:

  • To investigate the role of longevity and cell metabolism modifiers, specifically sirtuins and AMPK, in modulating PABPN1 toxicity.
  • To identify potential therapeutic targets for OPMD by examining the effects of modulating these pathways.

Main Methods:

  • Utilized a PABPN1 nematode model exhibiting muscle degeneration and abnormal motility.
  • Assessed the impact of altering the dosage of sir-2.1 (SIRT1) and its downstream effectors, daf-16 (FoxO) and aak-2 (AMPK).
  • Examined the effects of the Sir2 inhibitor sirtinol and the activator resveratrol on PABPN1 toxicity in both nematodes and mammalian cells.

Main Results:

  • Increased dosage of sir-2.1 exacerbated muscle pathology in nematodes, dependent on daf-16 and aak-2.
  • Null mutants of sir-2.1, daf-16, and aak-2 conferred protection against muscle degeneration.
  • Sirtinol demonstrated a protective effect, dependent on daf-16, while resveratrol aggravated pathology, dependent on aak-2.
  • Sirtinol promoted the survival of mammalian cells expressing mutant PABPN1, whereas resveratrol decreased it.

Conclusions:

  • Inhibition of Sir2 and AMPK represents a promising therapeutic strategy for muscle protection in OPMD.
  • This study highlights the potential of targeting cell maintenance networks for treating polyalanine diseases like OPMD.
  • Modulators of longevity and cell metabolism offer a druggable approach to combat PABPN1-induced proteotoxicity.

More Related Videos

Isolating Potentiated Hsp104 Variants Using Yeast Proteinopathy Models08:44

Isolating Potentiated Hsp104 Variants Using Yeast Proteinopathy Models

Published on: November 11, 2014

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Satellite Stem Cells and Muscular Dystrophy01:21

Satellite Stem Cells and Muscular Dystrophy

Satellite stem cells or myosatellite cells are quiescent stem cells that Alexander Mauro first identified in 1961. These cells are located between the sarcolemma, the plasma membrane of muscle fibers, and the basal lamina, the connective tissue sheath covering it. These mononucleated cells are activated in response to muscle injury, can transform into myoblasts, and may form or repair muscle fibers. Myosatellite cells can provide additional myonuclei for muscle regeneration or return to a...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...