Haploinsufficiency of AFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named m-AAA proteases. These complexes ensure protein quality control in the inner membrane, jointly with a chaperone-like activity on the respiratory chain complexes. Despite coassembling in the same complex, mutations of either paraplegin or AFG3L2 cause two different neurodegenerative disorders. Indeed, mutations of paraplegin are responsible for a recessive form of hereditary spastic paraplegia, whereas mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28). In this work, we report that the mouse model haploinsufficient for Afg3l2 recapitulates important pathophysiological features of the human disease, thus representing the first SCA28 model. Furthermore, we propose a pathogenetic mechanism in which respiratory chain dysfunction and increased reactive oxygen species production caused by Afg3l2 haploinsufficiency lead to dark degeneration of Purkinje cells and cerebellar dysfunction.

[1]  E. Rugarli,et al.  Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration. , 2009, Human molecular genetics.

[2]  Michael P. Murphy,et al.  How mitochondria produce reactive oxygen species , 2008, The Biochemical journal.

[3]  M. Mattson,et al.  Mitochondria in Neuroplasticity and Neurological Disorders , 2008, Neuron.

[4]  O. Bizzozero,et al.  Cytoskeletal protein carbonylation and degradation in experimental autoimmune encephalomyelitis , 2008, Journal of neurochemistry.

[5]  J. Guénet,et al.  The Mitochondrial Protease AFG3L2 Is Essential for Axonal Development , 2008, The Journal of Neuroscience.

[6]  T. Langer,et al.  Protein Degradation within Mitochondria: Versatile Activities of AAA Proteases and Other Peptidases , 2007, Critical reviews in biochemistry and molecular biology.

[7]  I. Reynolds,et al.  Mitochondrial trafficking and morphology in healthy and injured neurons , 2006, Progress in Neurobiology.

[8]  E. Rugarli,et al.  Variable and Tissue-Specific Subunit Composition of Mitochondrial m-AAA Protease Complexes Linked to Hereditary Spastic Paraplegia , 2006, Molecular and Cellular Biology.

[9]  A. Spada,et al.  Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport , 2006, Nature Neuroscience.

[10]  Harry T Orr,et al.  Targeted Deletion of a Single Sca8 Ataxia Locus Allele in Mice Causes Abnormal Gait, Progressive Loss of Motor Coordination, and Purkinje Cell Dendritic Deficits , 2006, The Journal of Neuroscience.

[11]  H. McBride,et al.  Mitochondria: More Than Just a Powerhouse , 2006, Current Biology.

[12]  M. Beal,et al.  The role of mitochondria in inherited neurodegenerative diseases , 2006, Journal of neurochemistry.

[13]  J. Julien,et al.  Activation of the p38MAPK cascade is associated with upregulation of TNF alpha receptors in the spinal motor neurons of mouse models of familial ALS , 2006, Molecular and Cellular Neuroscience.

[14]  J. Rothstein,et al.  Spectrin mutations cause spinocerebellar ataxia type 5 , 2006, Nature Genetics.

[15]  E. Rugarli,et al.  The m-AAA Protease Defective in Hereditary Spastic Paraplegia Controls Ribosome Assembly in Mitochondria , 2005, Cell.

[16]  Thomas Nyström,et al.  Role of oxidative carbonylation in protein quality control and senescence , 2005, The EMBO journal.

[17]  V. Cuomo,et al.  Transgenic mice expressing F3/contactin from the transient axonal glycoprotein promoter undergo developmentally regulated deficits of the cerebellar function , 2004, Neuroscience.

[18]  P. Brookes,et al.  Calcium, ATP, and ROS: a mitochondrial love-hate triangle. , 2004, American journal of physiology. Cell physiology.

[19]  J F Storm,et al.  Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[20]  C. Sotelo,et al.  Cellular and genetic regulation of the development of the cerebellar system , 2004, Progress in Neurobiology.

[21]  E. Rugarli,et al.  Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. , 2004, The Journal of clinical investigation.

[22]  J. Strahlendorf,et al.  AMPA-induced dark cell degeneration of cerebellar Purkinje neurons involves activation of caspases and apparent mitochondrial dysfunction , 2003, Brain Research.

[23]  A. Ballabio,et al.  Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia , 2003, The Journal of cell biology.

[24]  D. Nicholls,et al.  Interactions between mitochondrial bioenergetics and cytoplasmic calcium in cultured cerebellar granule cells. , 2003, Cell calcium.

[25]  R. Hawkes,et al.  Patterned Purkinje cell death in the cerebellum , 2003, Progress in Neurobiology.

[26]  E. Stadtman,et al.  Recent advances in the analysis of oxidized proteins , 2003, Amino Acids.

[27]  J. Crabbe,et al.  A mouse model of episodic ataxia type-1 , 2003, Nature Neuroscience.

[28]  M. Staufenbiel,et al.  Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation , 2002, Brain Research.

[29]  Masao Ito The molecular organization of cerebellar long-term depression , 2002, Nature Reviews Neuroscience.

[30]  C. Ware,et al.  Polyglutamine-Expanded Ataxin-7 Promotes Non-Cell-Autonomous Purkinje Cell Degeneration and Displays Proteolytic Cleavage in Ataxic Transgenic Mice , 2002, The Journal of Neuroscience.

[31]  J. Strahlendorf,et al.  Hypoxia induces an excitotoxic-type of dark cell degeneration in cerebellar Purkinje neurons , 2001, Neuroscience Research.

[32]  M. Filbin,et al.  Epitope-Tagged P0Glycoprotein Causes Charcot-Marie-Tooth–Like Neuropathy in Transgenic Mice , 2000, The Journal of cell biology.

[33]  J. Crawley Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests 1 Published on the World Wide Web on 2 December 1998. 1 , 1999, Brain Research.

[34]  Stephen B. Dunnett,et al.  Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation , 1999, The Journal of Neuroscience.

[35]  W. Neupert,et al.  Chaperone-like activity of the AAA domain of the yeast Yme1 AAA protease , 1999, Nature.

[36]  Y. Ueno,et al.  The process of ultrastructural changes from nuclei to apoptotic body , 1998, Virchows Archiv.

[37]  Ian J. Reynolds,et al.  Glutamate-induced neuron death requires mitochondrial calcium uptake , 1998, Nature Neuroscience.

[38]  W. Neupert,et al.  The formation of respiratory chain complexes in mitochondria is under the proteolytic control of the m‐AAA protease , 1998, The EMBO journal.

[39]  Sergio Cocozza,et al.  Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease , 1998, Cell.

[40]  E. Fisher,et al.  Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment , 1997, Mammalian Genome.

[41]  R. Nemni,et al.  β4 integrin and other Schwann cell markers in axonal neuropathy , 1996 .

[42]  Walter Neupert,et al.  The YTA10–12 Complex, an AAA Protease with Chaperone-like Activity in the Inner Membrane of Mitochondria , 1996, Cell.

[43]  H. Schägger,et al.  Analysis of molecular masses and oligomeric states of protein complexes by blue native electrophoresis and isolation of membrane protein complexes by two-dimensional native electrophoresis. , 1994, Analytical biochemistry.

[44]  J. Bereiter-Hahn,et al.  Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and fission of mitochondria , 1994, Microscopy research and technique.

[45]  R. McGivern,et al.  Altered adult sexual behavior in the male rat following chronic prenatal hypoxia. , 1993, Neurotoxicology and teratology.

[46]  H. Nijhout,et al.  In formation , 1988, Nature.

[47]  N W DUNHAM,et al.  A note on a simple apparatus for detecting neurological deficit in rats and mice. , 1957, Journal of the American Pharmaceutical Association. American Pharmaceutical Association.

[48]  Marco Seri,et al.  SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2. , 2006, Brain : a journal of neurology.

[49]  C. Gellera,et al.  SCA 28 , a novel form of autosomal dominant cerebellar ataxia on chromosome 18 p 11 . 22 – q 11 . 2 , 2005 .

[50]  S. Kalsner,et al.  One trial learning in the mouse , 2004, Psychopharmacologia.

[51]  R. Nemni,et al.  Beta 4 integrin and other Schwann cell markers in axonal neuropathy. , 1996, Glia.

[52]  B. Robinson Use of fibroblast and lymphoblast cultures for detection of respiratory chain defects. , 1996, Methods in enzymology.

[53]  E. Stadtman,et al.  Determination of carbonyl content in oxidatively modified proteins. , 1990, Methods in enzymology.