Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder

The role of astrocytes in neurodegenerative processes is increasingly appreciated. Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene. Using Cre/Lox mouse models, we found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of autophagic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo. Furthermore, in an ex vivo coculture assay, we observed that Sumf1−/− astrocytes failed to support the survival and function of wild-type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration. Compared with the astrocyte-specific deletion of Sumf1, the concomitant removal of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioral analysis of mice with astrocyte-specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed us to link a subset of neurological manifestations of MSD to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in MSD and that modulation of astrocyte function may impact disease course.

[1]  Pierre J Magistretti,et al.  Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. , 2011, Cell metabolism.

[2]  V. Shakkottai,et al.  Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration. , 2011, Human molecular genetics.

[3]  Milos Pekny,et al.  The Role of Attenuated Astrocyte Activation in Infantile Neuronal Ceroid Lipofuscinosis , 2011, The Journal of Neuroscience.

[4]  J. Cooper,et al.  Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease. , 2011, Human molecular genetics.

[5]  G. Lopez,et al.  Psychiatric and behavioral manifestations of lysosomal storage disorders , 2010, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[6]  B. Bilican,et al.  Cell-Mediated Neuroprotection in a Mouse Model of Human Tauopathy , 2010, The Journal of Neuroscience.

[7]  H. Paulson,et al.  Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration. , 2010, Human molecular genetics.

[8]  N. Mizushima,et al.  Methods in Mammalian Autophagy Research , 2010, Cell.

[9]  Chuan-en Wang,et al.  Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms , 2009, Proceedings of the National Academy of Sciences.

[10]  D. Kleinfeld,et al.  The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. , 2009, The Journal of clinical investigation.

[11]  P. Magistretti,et al.  The role of astroglia in neuroprotection , 2009, Dialogues in clinical neuroscience.

[12]  A. Ballabio,et al.  Lysosomal disorders: from storage to cellular damage. , 2009, Biochimica et biophysica acta.

[13]  D. Rubinsztein,et al.  Autophagy Inhibition Compromises Degradation of Ubiquitin-Proteasome Pathway Substrates , 2009, Molecular cell.

[14]  A. Ballabio,et al.  Proteoglycan desulfation determines the efficiency of chondrocyte autophagy and the extent of FGF signaling during endochondral ossification. , 2008, Genes & development.

[15]  D. Gutmann,et al.  Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis , 2008, Nature Neuroscience.

[16]  N. Mizushima,et al.  Chromosomal mapping of the GFP-LC3 transgene in GFP-LC3 mice , 2008, Autophagy.

[17]  Andrea Ballabio,et al.  A block of autophagy in lysosomal storage disorders. , 2008, Human molecular genetics.

[18]  J. Wagner,et al.  Hematopoietic cell therapy for metabolic disease. , 2007, The Journal of pediatrics.

[19]  A. Ballabio,et al.  Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency , 2007, Proceedings of the National Academy of Sciences.

[20]  C. Farina,et al.  Astrocytes are active players in cerebral innate immunity. , 2007, Trends in immunology.

[21]  J. Rothstein,et al.  Mechanisms of Disease: astrocytes in neurodegenerative disease , 2006, Nature Clinical Practice Neurology.

[22]  C. Morales,et al.  The sorting and trafficking of lysosomal proteins. , 2006, Histology and histopathology.

[23]  Masaaki Komatsu,et al.  Loss of autophagy in the central nervous system causes neurodegeneration in mice , 2006, Nature.

[24]  Hideyuki Okano,et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice , 2006, Nature.

[25]  M. Raíces,et al.  Correction: Uncoupling of Longevity and Telomere Length in C. elegans , 2005, PLoS Genetics.

[26]  M. Sofroniew,et al.  Reactive Astrocytes in Neural Repair and Protection , 2005, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[27]  Raymond A. Dwek,et al.  Storage solutions: treating lysosomal disorders of the brain , 2005, Nature Reviews Neuroscience.

[28]  A. Ballabio,et al.  Sulfatases and human disease. , 2005, Annual review of genomics and human genetics.

[29]  JoAnn Buchanan,et al.  Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease , 2005, PLoS genetics.

[30]  M. Nilsson,et al.  Astrocyte activation and reactive gliosis , 2005, Glia.

[31]  Peter Bross,et al.  The Metabolic and Molecular Basis of Inherited Disease: Protein Folding and Misfolding: the Role of Cellular Protein Quality Control Systems in Inherited Disorders , 2005 .

[32]  R. Sidman,et al.  A Mouse Model of Classical Late-Infantile Neuronal Ceroid Lipofuscinosis Based on Targeted Disruption of the CLN2 Gene Results in a Loss of Tripeptidyl-Peptidase I Activity and Progressive Neurodegeneration , 2004, The Journal of Neuroscience.

[33]  J. Wegiel,et al.  Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease , 2004, Neurobiology of Aging.

[34]  L. Naldini,et al.  Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. , 2004, The Journal of clinical investigation.

[35]  S. Walkley,et al.  Lysosomal Disorders of the Brain , 2004 .

[36]  J. Thompson,et al.  A model of mucopolysaccharidosis IIIB (Sanfilippo syndrome type IIIB): N-acetyl-α-D-glucosaminidase deficiency in Schipperke dogs , 2003, Journal of Inherited Metabolic Disease.

[37]  N. Rothwell,et al.  Inflammation in central nervous system injury. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[38]  A. Ballabio,et al.  The Multiple Sulfatase Deficiency Gene Encodes an Essential and Limiting Factor for the Activity of Sulfatases , 2003, Cell.

[39]  David A. Smith,et al.  Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. , 2003, Brain : a journal of neurology.

[40]  S. Ryazantsev,et al.  Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Kurt Zatloukal,et al.  p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. , 2002, The American journal of pathology.

[42]  Nancy A. Jenkins,et al.  Recombineering: a powerful new tool for mouse functional genomics , 2001, Nature Reviews Genetics.

[43]  J D Rothstein,et al.  Glutamate transporters in neurologic disease. , 2001, Archives of neurology.

[44]  Takeshi Noda,et al.  LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing , 2000, The EMBO journal.

[45]  R. Proia,et al.  Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[46]  J. Matsuda,et al.  Infiltration of Hematogenous Lineage Cells Into the Demyelinating Central Nervous System of Twitcher Mice , 2000, Journal of neuropathology and experimental neurology.

[47]  W. Walz.  Role of astrocytes in the clearance of excess extracellular potassium , 2000, Neurochemistry International.

[48]  R. Matalon,et al.  Sulfamidase Deficiency in a Family of Dachshunds: A Canine Model of Mucopolysaccharidosis IIIA (Sanfilippo A) , 1998, Pediatric Research.

[49]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[50]  P. C. Cross,et al.  Cell and Tissue Ultrastructure: A Functional Perspective , 1993 .

[51]  R. Brady,et al.  Lysosomal Storage Diseases , 1986, The Lancet.