2. Academic Validation
  3. Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis

Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis

  • Brain. 2024 Aug 28:awae270. doi: 10.1093/brain/awae270.
Delphine Sapaly 1,  Flore Cheguillaume 1,  Laure Weill 1,  Zoé Clerc 1,  Olivier Biondi 1 2,  Sabrina Bendris 1,  Céline Buon 3,  Rasha Slika 1,  Elsie Piller 1,  Venkat Krishnan Sundaram 4,  Andreia da Silva Ramos 4,  Maria Del Mar Amador 5 6,  Timothée Lenglet 5 7,  Rabab Debs 7,  Nadine Le Forestier 5 8,  Pierre-François Pradat 5,  François Salachas 5,  Lucette Lacomblez 5,  Adèle Hesters 5,  Didier Borderie 9 10,  David Devos 11 12,  Claude Desnuelle 12 13,  Anne-Sophie Rolland 11,  Baptiste Periou 14,  Stéphane Vasseur 15,  Maud Chapart 15,  Isabelle Le Ber 16,  Anne-Laure Fauret-Amsellem 17,  Stéphanie Millecamps 18,  Thierry Maisonobe 19,  Sarah Leonard-Louis 19,  Anthony Behin 20,  François-Jérôme Authier 14,  Teresinha Evangelista 19 20,  Frédéric Charbonnier 1,  Gaëlle Bruneteau 3 5 12,  PULSE study group
Affiliations

Affiliations

  • 1 University Paris Cité & Inserm UMR_S1124, 75270, Paris Cedex 06, France.
  • 2 Laboratoire de Biologie de l'Exercice pour la Performance et la Santé (LBEPS), UMR, Université d'Evry, IRBA, Université de Paris Saclay, 91025 Evry-Courcouronnes, France.
  • 3 Myology Center For Research, UMRS974, Sorbonne University, INSERM, 75013 Paris, France.
  • 4 Paul Flechsig Institute - Centre of Neuropathology and Brain Research, Faculty of Medicine, University of Leipzig, 04103, Leipzig, Germany.
  • 5 Sorbonne Université, APHP, Inserm, CNRS, Institut du Cerveau - Paris Brain Institute - ICM, Pitié-Salpêtrière Hospital, Paris ALS expert center, Department of NeurologyCIC Neurosciences, 75013 Paris, France.
  • 6 APHP, Genetic department, Pitié-Salpêtrière University Hospital, 75013 Paris, France.
  • 7 Neurophysiology Department, APHP, Pitié-Salpêtrière Hospital, 75013 Paris, France.
  • 8 Espaces Régional IdF et National de Réflexion Éthique-Maladies Neuro Évolutives, Université Paris Sud/Paris Saclay, 75010 Paris, France.
  • 9 Department of Biochemistry, APHP, Cochin Hospital, 75014 Paris, France.
  • 10 Faculty of Pharmacy, University Paris Cité & Inserm UMR_S1124, 75006 Paris, France.
  • 11 Pharmacology Department, University Hospital of Lille, Lille University, INSERM UMRS_1172, LICEND, 59000 Lille, France.
  • 12 Alliance on Clinical Trials for ALS-MND (ACT4ALS-MND), Neuroscience Clinical Investigation Center, Paris Brain Institute, 75013 Paris, France.
  • 13 Pasteur 2 Hospital - CHU de Nice, 06000 Nice, France.
  • 14 Créteil Paris Est University, INSERM, IMRB U955, and Reference centre for rare neuromuscular diseases, AP-HP, Henri Mondor Hospital 94010, 94010 Créteil, France.
  • 15 MyoBank AFM-Institut de Myologie, 75013 Paris, France.
  • 16 Reference centre for rare dementias, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France.
  • 17 Functional Unit of Cellular and Molecular Neurogenetics, Genetic Department, AP-HP Sorbonne University, Pitié-Salpêtrière Hospital, 75013 Paris, France.
  • 18 Sorbonne University, Paris Brain Institute, ICM, Inserm, CNRS, APHP, Pitié-Salpêtrière Hospital, DMU Neuroscience 6, 75013 Paris, France.
  • 19 Department of Neuropathology, Sorbonne University, APHP, Pitié-Salpêtrière Hospital, 75013 Paris, France.
  • 20 Reference Center for Muscle Diseases Paris-Est, Myology Institute, AP-HP, Pitié-Salpêtrière Hospital, 75013 Paris, France.
PMID: 39197036 DOI: 10.1093/brain/awae270
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole-body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, Cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle Cholesterol metabolism. We determined Cholesterol content and analyzed the expression of key determinants of the Cholesterol metabolism pathway in muscle biopsies from thirteen ALS patients and ten asymptomatic ALS-mutation gene carriers compared to sixteen controls. Using human control primary myotubes, we further investigated the potential contribution of Cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that Cholesterol accumulates in the skeletal muscle of ALS patients and that Cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal Cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for Cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified Cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that Cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.

Keywords

disease progression; metabolism; presymptomatic stage.

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