Conformational Diseases: Structural Studies of Aggregation of Polyglutamine Proteins

Elena      Papaleo; Gaetano      Invernizzi

doi:10.2174/157340911793743574

Abstract

Protein misfolding and aggregation into insoluble amyloid deposits are often associated with neurodegenerative disorders. In particular, the polyglutamine (polyQ) diseases are inherited disorders triggered by the expansion of the polyQ tract over its physiological length in the involved protein. The molecular mechanism of aggregation from the native protein into amyloids involves several steps including protein misfolding, aggregation into oligomers, which seems to be the most toxic species, and, finally rearrangements into mature fibrils. In the present contribution, we review studies, integrating computational and experimental approaches, of polyQ proteins, as well as of the details of the complicate aggregation mechanisms in which aberrant form of polyQ proteins are involved. These aspects are of crucial relevance for a complete understanding of the onset of polyQ conformational diseases and can also shed light on putative therapeutic targets and future development of aggregation inhibitors.

Keywords: polyQ disease, protein aggregation, protein misfolding, conformational disease, molecular dynamics simulations, aggregation inhibitors, huntingtin, ataxin, polyglutamine (polyQ) diseases, sheet supramolecular structures, Alzheimer's, Parkinson's, amyloids, Amyloid fibrils, protofilaments, hydrogen-bonded amyloid core, antiparallel (AP) structures, ataxins, atrophin-1, synuclein, A amyloid peptide, super-oxide dismutase 1 (SOD1), NMR, cryo-electron microscopy, transmission electron microscopy, electron paramagnetic resonance, fluorescence resonance energy transfer, mutational approaches, size-exclusion chromatography, hydrogen exchange, protein intermediate resolution model (PRIME), polyglutamine expansions, huntingtin (Htt), ataxin-3 (AT-3), ataxin-1 (AT-1), GABAergic medium spiny striatal neurons (MSN), MATLEKLMKAFESLKSF, Nt17, CAG repeat diseases, AXH domain, HBP1, SCA1, CAT, CAG, Machado Joseph Disease, de-ubiquitinating activity, polyubiquitin chains, histone acetyltransferase, N-terminal Josephin domain, ubiquitin interacting motifs (UIMs), 2-3 harpin, K48-linked tetra-ubiquitin chains, Gln, Asn-rich sequences, Sup34-N, Ure2p, circular dichroism, electron microscopy, X-ray diffraction, polyGln tract, Q41 peptide, GNNQQNY, isoenergetic fibrillar form, single molecule force-clamp spectroscopy, Monomeric polyglutamine, OPLSAA/L force field, mesoglobules, Molten oligomers, peptide-rich micro-phases, non-aggregating, aggregating peptides, Transmission Electron Microscopy (TEM), Q20, Q24, aggregates, chimeric proteins, Gln-repeats, chimeric chymotrypsin inhibitor 2 (CI2)-polyQ, pathogenic threshold, non-amyloidogenic protein, replica-exchange MD (REMD), Optimized Potential for Effective Peptide (OPEP), 2 proline helix-breaker residues, UV-CD spectroscopy, polyPro type II-like helix (PPIIlike), arginine [R], lysine [K], aspartate [D], glutamate [E], TANGO algorithm confirms, p53, Q22 peptide, His-Gln-His sequence, AT-3(QHQ), AT-3(Q15), AT-3(Q64), Size Exclusion Chromatography (SEC), heat shock transcription factor 1 (HSF1), geldanamycin, polyQ binding peptide 1 (QPBP1), EGCG (epigallocatechin-3-gallate)