Huntingtin Spheroids and Protofibrils as Precursors in Polyglutamine Fibrilization*

The pathology of Huntington's disease is characterized by neuronal degeneration and inclusions containing N-terminal fragments of mutant huntingtin (htt). To study htt aggregation, we examined purified htt fragments in vitro, finding globular and protofibrillar intermediates participating in the genesis of mature fibrils. These intermediates were high in β-structure. Furthermore, Congo Red, a dye that stains amyloid fibrils, prevented the assembly of mutant htt into mature fibrils, but not the formation of protofibrils. Other proteins capable of forming ordered aggregates, such as amyloid β and α-synuclein, form similar intermediates, suggesting that the mechanisms of mutant htt aggregation and possibly htt toxicity may overlap with other neurodegenerative disorders.

[1]  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.

[2]  C. Bustamante,et al.  Wrapping of DNA around the E.coli RNA polymerase open promoter complex , 1999, The EMBO journal.

[3]  B. Singh,et al.  Infrared analysis of peptides and proteins : principles and applications , 1999 .

[4]  Hans Lehrach,et al.  Huntingtin-Encoded Polyglutamine Expansions Form Amyloid-like Protein Aggregates In Vitro and In Vivo , 1997, Cell.

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

[6]  E. Altschuler,et al.  Random coil conformation for extended polyglutamine stretches in aqueous soluble monomeric peptides. , 2009, The journal of peptide research : official journal of the American Peptide Society.

[7]  C. Finch,et al.  Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? , 2001, Trends in Neurosciences.

[8]  P. Patterson,et al.  Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G P Bates,et al.  Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[11]  S. W. Davies,et al.  Intranuclear Neuronal Inclusions in Huntington's Disease and Dentatorubral and Pallidoluysian Atrophy: Correlation between the Density of Inclusions andIT15CAG Triplet Repeat Length , 1998, Neurobiology of Disease.

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

[13]  F. Fu,et al.  Role of zinc in the structure and toxic activity of botulinum neurotoxin. , 1998, Biochemistry.

[14]  H. Zoghbi,et al.  Glutamine repeats and neurodegeneration. , 2000, Annual review of neuroscience.

[15]  P S Harper,et al.  Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. , 1996, American journal of human genetics.

[16]  C. Ross,et al.  Preparation of human cDNAs encoding expanded polyglutamine repeats , 1999, Neuroscience Letters.

[17]  James F. Gusella,et al.  Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease , 2000, Nature Reviews Neuroscience.

[18]  J. Penney,et al.  Trinucleotide repeat length instability and age of onset in Huntington's disease , 1993, Nature Genetics.

[19]  C. Ross,et al.  Isolation of a 40-kDa Huntingtin-associated Protein* , 2001, The Journal of Biological Chemistry.

[20]  H. Paulson.  Toward an Understanding of Polyglutamine Neurodegeneration , 2000, Brain pathology.

[21]  H. Lehrach,et al.  Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Peter T. Lansbury,et al.  Assembly of Aβ Amyloid Protofibrils: An in Vitro Model for a Possible Early Event in Alzheimer's Disease† , 1999 .

[23]  R. Wetzel,et al.  Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. , 2001, Journal of molecular biology.

[24]  R. Wetzel,et al.  Conformational Abs recognizing a generic amyloid fibril epitope , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  P. Lansbury,et al.  Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse alpha-synuclein. , 2000, Biochemistry.

[26]  S. Lindquist,et al.  Nucleated conformational conversion and the replication of conformational information by a prion determinant. , 2000, Science.

[27]  Peter T. Lansbury,et al.  Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct , 2001, Science.

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

[29]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[30]  S. Sisodia.  Nuclear Inclusions in Glutamine Repeat Disorders Are They Pernicious, Coincidental, or Beneficial? , 1998, Cell.

[31]  Annalisa Pastore,et al.  Solution structure of polyglutamine tracts in GST‐polyglutamine fusion proteins , 2002, FEBS letters.

[32]  C. Dobson,et al.  Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases , 2002, Nature.

[33]  D. Housman,et al.  A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila , 2002, Nature Genetics.