Huntingtin Aggregate-Associated Axonal Degeneration is an Early Pathological Event in Huntington's Disease Mice

Huntington's disease (HD) is characterized by the selective loss of striatal projection neurons. In early stages of HD, neurodegeneration preferentially occurs in the lateral globus pallidus (LGP) and substantia nigra (SN), two regions in which the axons of striatal neurons terminate. Here we report that in mice expressing full-length mutant huntingtin and modeling early stages of HD, neuropil aggregates form preferentially in the LGP and SN. The progressive formation of these neuropil aggregates follows intranuclear accumulation of mutant huntingtin and becomes prominent from 11 to 27 months after birth. Neuropil aggregates, but no intranuclear inclusions, were observed in the LGP and SN, suggesting that huntingtin aggregates are formed in the axons of striatal projection neurons. In the LGP and SN, we observed degenerated axons in which huntingtin aggregates were associated with dark, swollen organelles that resemble degenerated mitochondria. Neuritic aggregates also form in cultured striatal neurons expressing mutant huntingtin, block protein transport in neurites, and cause neuritic degeneration before nuclear DNA fragmentation occurs. These findings suggest that the early neuropathology of HD originates from axonal dysfunction and degeneration associated with huntingtin aggregates.

[1]  C A Ross,et al.  Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity , 2001, Science.

[2]  Takeshi Tokuhisa,et al.  Dissection of Autophagosome Formation Using Apg5-Deficient Mouse Embryonic Stem Cells , 2001, The Journal of cell biology.

[3]  P. Shelbourne,et al.  Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington's disease? , 2000, Human molecular genetics.

[4]  M. DiFiglia,et al.  Huntingtin Expression Stimulates Endosomal–Lysosomal Activity, Endosome Tubulation, and Autophagy , 2000, The Journal of Neuroscience.

[5]  He Li,et al.  Expression of Huntingtin-Associated Protein-1 in Neuronal Cells Implicates a Role in Neuritic Growth , 2000, Molecular and Cellular Neuroscience.

[6]  He Li,et al.  Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity , 2000, Nature Genetics.

[7]  M. Beal.  Energetics in the pathogenesis of neurodegenerative diseases , 2000, Trends in Neurosciences.

[8]  S B Dunnett,et al.  Abnormal Synaptic Plasticity and Impaired Spatial Cognition in Mice Transgenic for Exon 1 of the Human Huntington's Disease Mutation , 2000, The Journal of Neuroscience.

[9]  C A Ross,et al.  Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. , 2000, Human molecular genetics.

[10]  S. Benzer,et al.  Genetic suppression of polyglutamine toxicity in Drosophila. , 2000, Science.

[11]  M. MacDonald,et al.  Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. , 2000, Human molecular genetics.

[12]  R. Shadmehr,et al.  Motor disorder in Huntington's disease begins as a dysfunction in error feedback control , 2000, Nature.

[13]  A H Schapira,et al.  Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse , 2000, Annals of neurology.

[14]  S. Hersch,et al.  Huntingtin aggregates may not predict neuronal death in Huntington's disease , 1999 .

[15]  H. Paulson,et al.  Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70 , 1999, Nature Genetics.

[16]  Carlos Cepeda,et al.  Enhanced sensitivity to N‐methyl‐D‐aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease , 1999, Journal of neuroscience research.

[17]  S. Snyder,et al.  Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization , 1999, Nature Medicine.

[18]  Shihua Li,et al.  Cellular Defects and Altered Gene Expression in PC12 Cells Stably Expressing Mutant Huntingtin , 1999, The Journal of Neuroscience.

[19]  D. Arnold.  Magnetic resonance spectroscopy: imaging axonal damage in MS , 1999, Journal of Neuroimmunology.

[20]  G P Bates,et al.  Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice. , 1999, Human molecular genetics.

[21]  B D Trapp,et al.  Axonal pathology in multiple sclerosis: relationship to neurologic disability. , 1999, Current opinion in neurology.

[22]  H. Johnston,et al.  A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. , 1999, Human molecular genetics.

[23]  Claire-Anne Gutekunst,et al.  A YAC Mouse Model for Huntington’s Disease with Full-Length Mutant Huntingtin, Cytoplasmic Toxicity, and Selective Striatal Neurodegeneration , 1999, Neuron.

[24]  R. Myers,et al.  Impaired synaptic plasticity in mice carrying the Huntington's disease mutation. , 1999, Human molecular genetics.

[25]  Claire-Anne Gutekunst,et al.  Nuclear and Neuropil Aggregates in Huntington’s Disease: Relationship to Neuropathology , 1999, The Journal of Neuroscience.

[26]  D. Borchelt,et al.  Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. , 1999, Human molecular genetics.

[27]  J. Blenis,et al.  Caspase-8 Is Required for Cell Death Induced by Expanded Polyglutamine Repeats , 1999, Neuron.

[28]  A. Schapira,et al.  Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia and Friedreich's ataxia. , 1999, Biochimica et biophysica acta.

[29]  J. Penney,et al.  Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. , 1999, Journal of neuropathology and experimental neurology.

[30]  S. Hersch,et al.  Huntington aggregates may not predict neuronal death in Huntington's disease. , 1999, Annals of neurology.

[31]  W. Trojaborg.  Acute and chronic neuropathies: new aspects of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, an overview and an update. , 1998, Electroencephalography and clinical neurophysiology.

[32]  Harry T Orr,et al.  Ataxin-1 Nuclear Localization and Aggregation Role in Polyglutamine-Induced Disease in SCA1 Transgenic Mice , 1998, Cell.

[33]  Steven Finkbeiner,et al.  Huntingtin Acts in the Nucleus to Induce Apoptosis but Death Does Not Correlate with the Formation of Intranuclear Inclusions , 1998, Cell.

[34]  Lisa Garrett,et al.  Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA , 1998, Nature Genetics.

[35]  S. W. Davies,et al.  Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. W. Davies,et al.  Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. , 1997, Science.

[37]  Mark Turmaine,et al.  Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation , 1997, Cell.

[38]  M. Beal,et al.  Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia , 1997, Annals of neurology.

[39]  Vijay Sawlani,et al.  MRI demonstration of Wallerian degeneration in various intracranial lesions and its clinical implications , 1997, Journal of the Neurological Sciences.

[40]  Gajdusĕk Dc,et al.  Myelinated axon undergoes complete demyelination in the panencephalopathic--but it is merely subjected to the Wallerian degeneration in the polioencephalopathic type of transmissible spongiform encephalopathies. , 1997 .

[41]  P. Liberski,et al.  Myelinated axon undergoes complete demyelination in the panencephalopathic--but it is merely subjected to the Wallerian degeneration in the polioencephalopathic type of transmissible spongiform encephalopathies. , 1997, Polish journal of pathology : official journal of the Polish Society of Pathologists.

[42]  S. W. Davies,et al.  Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice , 1996, Cell.

[43]  E. Richfield,et al.  Preferential loss of preproenkephalin versus preprotachykinin neurons from the striatum of Huntington's disease patients , 1995, Annals of neurology.

[44]  G. Slama,et al.  Severe early-onset polyneuropathy in insulin-dependent diabetes mellitus. A clinical and pathological study. , 1992, The New England journal of medicine.

[45]  J. Penney,et al.  Preferential loss of striato‐external pallidal projection neurons in presymptomatic Huntington's disease , 1992, Annals of neurology.

[46]  A. Graybiel.  Neurotransmitters and neuromodulators in the basal ganglia , 1990, Trends in Neurosciences.

[47]  W. Dunn,et al.  Studies on the mechanisms of autophagy: formation of the autophagic vacuole , 1990, The Journal of cell biology.

[48]  J. Penney,et al.  Abnormalities of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington's disease. , 1990, The New England journal of medicine.

[49]  J. Penney,et al.  Differential loss of striatal projection neurons in Huntington disease. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. B. Martin,et al.  Selective sparing of a class of striatal neurons in Huntington's disease. , 1985, Science.

[51]  R. Ferrante,et al.  Neuropathological Classification of Huntington's Disease , 1985, Journal of neuropathology and experimental neurology.

[52]  G. Graveland,et al.  Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease. , 1985, Science.