Dopamine Oxidation Products as Mitochondrial Endotoxins, a Potential Molecular Mechanism for Preferential Neurodegeneration in Parkinson's Disease.

The preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta is responsible for the motor impairment associated with Parkinson's disease. Dopamine is a highly reactive molecule, which is usually stored inside synaptic vesicles where it is stabilized by the ambient low pH. However, free cytosolic dopamine can auto-oxidize, generating reactive oxygen species, and lead to the formation of toxic quinones.

Folding Landscape of Mutant Huntingtin Exon1: Diffusible Multimers, Oligomers and Fibrils, and No Detectable Monomer.

Expansion of the polyglutamine (polyQ) track of the Huntingtin (HTT) protein above 36 is associated with a sharply enhanced risk of Huntington's disease (HD). Although there is general agreement that HTT toxicity resides primarily in N-terminal fragments such as the HTT exon1 protein, there is no consensus on the nature of the physical states of HTT exon1 that are induced by polyQ expansion, nor on which of these states might be responsible for toxicity. One hypothesis is that polyQ expansion induces an alternative, toxic conformation in the HTT exon1 monomer.

HCN hyperpolarization-activated cation channels strengthen virtual nicotinic EPSPs and thereby elevate synaptic amplification in rat sympathetic neurons.

The influence of hyperpolarization-activated cation current (h-current; Ih) upon synaptic integration in paravertebral sympathetic neurons was studied together with expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) subunit isoforms. All four HCN subunits were detected in homogenates of the rat superior cervical ganglion (SCG) using the PCR to amplify reverse-transcribed messenger RNAs (RT-PCR) and using quantitative PCR. Voltage clamp recordings from dissociated SCG neurons at 35°C detected Ih in all cells, with a maximum hyperpolarization-activated cation conductance of 1.

D-polyglutamine amyloid recruits L-polyglutamine monomers and kills cells.

Polyglutamine (polyQ) amyloid fibrils are observed in disease tissue and have been implicated as toxic agents responsible for neurodegeneration in expanded CAG repeat diseases such as Huntington's disease. Despite intensive efforts, the mechanism of amyloid toxicity remains unknown. As a novel approach to probing polyQ toxicity, we investigate here how some cellular and physical properties of polyQ amyloid vary with the chirality of the glutamine residues in the polyQ.

β-hairpin-mediated nucleation of polyglutamine amyloid formation.

The conformational preferences of polyglutamine (polyQ) sequences are of major interest because of their central importance in the expanded CAG repeat diseases that include Huntington's disease. Here, we explore the response of various biophysical parameters to the introduction of β-hairpin motifs within polyQ sequences. These motifs (tryptophan zipper, disulfide, d-Pro-Gly, Coulombic attraction, l-Pro-Gly) enhance formation rates and stabilities of amyloid fibrils with degrees of effectiveness well correlated with their known abilities to enhance β-hairpin formation in other peptides.

Inhibiting the nucleation of amyloid structure in a huntingtin fragment by targeting α-helix-rich oligomeric intermediates.

Although oligomeric intermediates are transiently formed in almost all known amyloid assembly reactions, their mechanistic roles are poorly understood. Recently, we demonstrated a critical role for the 17-amino-acid N-terminus (htt(NT) segment) of huntingtin (htt) in the oligomer-mediated amyloid assembly of htt N-terminal fragments. In this mechanism, the htt(NT) segment forms the α-helix-rich core of the oligomers, leaving much of the polyglutamine (polyQ) segment disordered and solvent-exposed.

Molecular characterization of dopamine-derived quinones reactivity toward NADH and glutathione: implications for mitochondrial dysfunction in Parkinson disease.

Oxidative stress and mitochondrial dysfunction, especially at the level of complex I of the electronic transport chain, have been proposed to be involved in the pathogenesis of Parkinson disease (PD). A plausible source of oxidative stress in nigral dopaminergic neurons is the redox reactions that specifically involve dopamine (DA) and produce various toxic molecules, i.e.