Severe neurodegeneration with impaired autophagy mechanism triggered by ostm1 deficiency.
Loss of Ostm1 leads to the most severe form of osteopetrosis in mice and humans. Because functional rescue of the osteopetrotic defect in these mice extended their lifespan from ∼3 weeks to 6 weeks, this unraveled a second essential role of Ostm1. We discovered that Ostm1 is highly expressed in the mouse brain in neurons, microglia, and astrocytes. At 3-4 weeks of age, mice with Ostm1 loss showed 3-10-fold stimulation of reactive gliosis, with an increased astrocyte cell population and microglia activation. This inflammatory response was associated with marked retinal photoreceptor degeneration and massive neuronal loss in the brain. Intracellular characterization of neurons revealed abnormal storage of carbohydrates, lipids, and ubiquitinated proteins, combined with marked accumulation of autophagosomes that causes frequent axonal swelling. Stimulation of autophagy was provided by specific markers and by significant down-regulation of the mammalian target of rapamycin signaling, identifying a cellular pathologic mechanism. A series of transgenic mouse lines specifically targeted to distinct central nervous system cell subpopulations determined that Ostm1 has a primary and autonomous role in neuronal homeostasis. Complete functional complementation demonstrated that the development of severe and rapid neurodegeneration in these mice is independent of the hematopoietic lineage and has clinical implications for treatment of osteopetrosis. Importantly, this study establishes a novel neurodegenerative mouse model critical for understanding the multistep pathogenic cascade of cellular autophagy disorders toward therapeutic strategy design.
From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
Céline
C
Héraud
From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
Adam
A
Griffiths
From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
Subramanya N M
SN
Pandruvada
the Department of Otolaryngology, Göttingen University Medical Center, D-37075 Göttingen, Germany, and the Department of Molecular Neurobiology, Max-Planck-Institute for Experimental Medicine, D-37075 Göttingen, Germany.
Manfred W
MW
Kilimann
From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
Monica
M
Pata
From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada, vacherj@ircm.qc.ca.
Jean
J
Vacher
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001343:Autophagy; D006410:Hematopoiesis; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D044767:Ubiquitin-Protein Ligases; D000099232:Proto-Oncogene Protein Spi-1; C489946:OSTM1 protein, human
Autophagy; Neurodegeneration; Neurons; Transgenic Mice; mTOR