From Alzheimer to Huntington: why is a structural understanding so difficult?

An increasing family of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, prion encephalopathies and cystic fibrosis is associated with aggregation of misfolded polypeptide chains which are toxic to the cell. Knowledge of the three‐dimensional structure of the proteins implicated is essential for understanding why and how endogenous proteins may adopt a non‐native fold. Yet, structural work has been hampered by the difficulty of handling proteins insoluble or prone to aggregation, and at the same time that is why it is interesting to study these molecules. In this review, we compare the structural knowledge accumulated for two paradigmatic misfolding disorders, Alzheimer's disease (AD) and the family of poly‐glutamine diseases (poly‐Q) and discuss some of the hypotheses suggested for explaining aggregate formation. While a common mechanism between these pathologies remains to be proven, a direct comparison may help in designing new strategies for approaching their study.

[1]  R. Brandt,et al.  Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain , 1995, The Journal of cell biology.

[2]  E. Kraepelin.  Psychiatrie : ein Lehrbuch für Studi[e]rende und Aerzte , 1976 .

[3]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[4]  D. Craik,et al.  Solution structure of amyloid beta-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is? , 1998, Biochemistry.

[5]  G. Glenner,et al.  Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein , 1984 .

[6]  H. Paulson,et al.  Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold. , 1999, American journal of human genetics.

[7]  Xiantao Wang,et al.  Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis. , 2002, Brain : a journal of neurology.

[8]  J. Octave,et al.  Intracellular Amyloid-β1–42, but Not Extracellular Soluble Amyloid-β Peptides, Induces Neuronal Apoptosis* , 2002, The Journal of Biological Chemistry.

[9]  A. Mochizuki,et al.  Aβ42-positive non-pyramidal neurons around amyloid plaques in Alzheimer's disease , 2000, The Lancet.

[10]  E. Mandelkow,et al.  Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Dyer,et al.  Mutant protein in Huntington disease is resistant to proteolysis in affected brain , 2001, Nature Genetics.

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

[13]  J T Finch,et al.  Amyloid fibers are water-filled nanotubes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Damberg,et al.  Reversible Random Coil to β‐Sheet Transition and the Early Stage of Aggregation of the Aβ(12—28) Fragment from the Alzheimer Peptide. , 2000 .

[15]  H. Wiśniewski,et al.  The microtubule-associated protein tau forms a triple-stranded left-hand helical polymer. , 1991, The Journal of biological chemistry.

[16]  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.

[17]  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.

[18]  Ralf Langen,et al.  Structural and Dynamic Features of Alzheimer's Aβ Peptide in Amyloid Fibrils Studied by Site-directed Spin Labeling* , 2002, The Journal of Biological Chemistry.

[19]  J. Sodroski,et al.  Stimulation of Enveloped Virus Infection by β-Amyloid Fibrils* , 2002, The Journal of Biological Chemistry.

[20]  K. Fischbeck,et al.  Toxic Proteins in Neurodegenerative Disease , 2002, Science.

[21]  Rodger Staden,et al.  Polar zippers , 1993, Current Biology.

[22]  R. Riek,et al.  NMR studies in aqueous solution fail to identify significant conformational differences between the monomeric forms of two Alzheimer peptides with widely different plaque-competence, A beta(1-40)(ox) and A beta(1-42)(ox). , 2001, European Journal of Biochemistry.

[23]  H. Shao,et al.  Solution structures of micelle-bound amyloid beta-(1-40) and beta-(1-42) peptides of Alzheimer's disease. , 1999, Journal of molecular biology.

[24]  B. Kagan,et al.  Polyglutamine‐induced ion channels: a possible mechanism for the neurotoxicity of huntington and other CAG repeat diseases , 2000, Journal of neuroscience research.

[25]  K. Iwata,et al.  The Alzheimer's peptide a beta adopts a collapsed coil structure in water. , 2000, Journal of structural biology.

[26]  R. Lal,et al.  Amyloid β protein forms ion channels: implications for Alzheimer's disease pathophysiology , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  V. Muñoz,et al.  Alpha-helix structure in Alzheimer's disease aggregates of tau-protein. , 2002, Biochemistry.

[28]  Dale E. Bredesen,et al.  Caspase Cleavage of Gene Products Associated with Triplet Expansion Disorders Generates Truncated Fragments Containing the Polyglutamine Tract* , 1998, The Journal of Biological Chemistry.

[29]  R. Snell,et al.  Amyloid-like inclusions in Huntington’s disease , 2000, Neuroscience.

[30]  R. Albin,et al.  Ectopically Expressed CAG Repeats Cause Intranuclear Inclusions and a Progressive Late Onset Neurological Phenotype in the Mouse , 1997, Cell.

[31]  R. Wetzel,et al.  Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. , 2002, Human molecular genetics.

[32]  J. J. Balbach,et al.  Supramolecular Structure in Full-Length Alzheimer's β-Amyloid Fibrils: Evidence for a Parallel β-Sheet Organization from Solid-State Nuclear Magnetic Resonance , 2002 .

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

[34]  J. Trojanowski,et al.  Neurodegenerative tauopathies. , 2001, Annual review of neuroscience.

[35]  A. Gräslund,et al.  Reversible Random Coil to β-Sheet Transition and the Early Stage of Aggregation of the Aβ(12−28) Fragment from the Alzheimer Peptide , 2000 .

[36]  E. Mandelkow,et al.  Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. , 1994, The Journal of biological chemistry.

[37]  C. Masters,et al.  The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. D'Ursi,et al.  Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain. , 2002, European journal of biochemistry.

[39]  C. Dobson.  Protein misfolding, evolution and disease. , 1999, Trends in biochemical sciences.

[40]  G. Bloom,et al.  Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules , 1999, The Journal of Biological Chemistry.

[41]  R. Brasseur,et al.  Fusogenic Properties of the C-terminal Domain of the Alzheimer β-Amyloid Peptide* , 1996, The Journal of Biological Chemistry.

[42]  A. Pastore,et al.  Glutamine repeats: structural hypotheses and neurodegeneration. , 2001, Biochemical Society transactions.

[43]  R. Crowther,et al.  Image reconstruction of the Alzheimer paired helical filament. , 1985, The EMBO journal.

[44]  D. Butterfield,et al.  Review: Alzheimer's amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. , 2000, Journal of structural biology.

[45]  D. Selkoe,et al.  X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[46]  K. Kolle.  Psychiatrie : ein Lehrbuch für Studierende und Ärzte , 1962 .

[47]  Richard H. Lathrop,et al.  Modeling Protein Homopolymeric Repeats: Possible Polyglutamine Structural Motifs for Huntington's Disease , 1998, ISMB.

[48]  J. Ávila,et al.  Characterization by atomic force microscopy and cryoelectron microscopy of tau polymers assembled in Alzheimer's disease. , 2001, Journal of Alzheimer's disease : JAD.

[49]  W. Welch,et al.  Glucocorticoid modulation of androgen receptor nuclear aggregation and cellular toxicity is associated with distinct forms of soluble expanded polyglutamine protein. , 2001, Human molecular genetics.

[50]  A. Cattaneo,et al.  The solution structure of the C‐terminal segment of tau protein , 2000, Journal of peptide science : an official publication of the European Peptide Society.

[51]  G. Glenner,et al.  Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. , 1984, Biochemical and biophysical research communications.

[52]  B. Ghetti,et al.  Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: A New Group of Tauopathies , 1998, Brain pathology.

[53]  P. Markiewicz,et al.  Paired Helical Filaments Are Twisted Ribbons Composed of Two Parallel and Aligned Components: Image Reconstruction and Modeling of Filament Structure Using Atomic Force Microscopy , 1997, Journal of neuropathology and experimental neurology.

[54]  R. Lal,et al.  Amyloid β Protein-(1–42) Forms Calcium-permeable, Zn2+-sensitive Channel* , 1998, The Journal of Biological Chemistry.

[55]  H. Monoi.  New tubular single-stranded helix of poly-L-amino acids suggested by molecular mechanics calculations: I. Homopolypeptides in isolated environments. , 1995, Biophysical journal.

[56]  L. Serpell,et al.  Common core structure of amyloid fibrils by synchrotron X-ray diffraction. , 1997, Journal of molecular biology.

[57]  H. Minakata,et al.  Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases. , 2000, Biophysical journal.

[58]  K. Lindenberg,et al.  Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. , 2002, Molecular cell.

[59]  H. Lehrach,et al.  Folding of oligoglutamines: a theoretical approach based upon thermodynamics and molecular mechanics. , 1999, Journal of biomolecular structure & dynamics.

[60]  H. Shao,et al.  Solution Structures of Micelle-bound Amyloid b-( 1-40 ) and b-( 1-42 ) Peptides of Alzheimer ' s Disease , 1998 .

[61]  K. Beyreuther,et al.  Structure of amyloid A4-(1-40)-peptide of Alzheimer's disease. , 1995, European journal of biochemistry.

[62]  D. Cleveland,et al.  Going new places using an old MAP: tau, microtubules and human neurodegenerative disease. , 2001, Current opinion in cell biology.

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

[64]  C. Sigurdson,et al.  [Prion diseases?]. , 1985, Deutsche medizinische Wochenschrift.

[65]  L. Serpell,et al.  Alzheimer's amyloid fibrils: structure and assembly. , 2000, Biochimica et biophysica acta.

[66]  C. Barbato,et al.  Tau Cleavage and Dephosphorylation in Cerebellar Granule Neurons Undergoing Apoptosis , 1998, The Journal of Neuroscience.

[67]  Z. Qin,et al.  Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis , 2001, Proceedings of the National Academy of Sciences of the United States of America.