8 research outputs found
Increased ω6-Containing Phospholipids and Primary ω6 Oxidation Products in the Brain Tissue of Rats on an ω3-Deficient Diet
Model-based Quantification of Cerebral Hemodynamics as a Physiomarker for Alzheimer’s Disease?
Solid-state NMR structure of a pathogenic fibril of full-length human alpha-synuclein
Misfolded a-synuclein amyloid fibrils are the principal components of Lewy bodies and neurites, hallmarks of Parkinson’s disease
(PD). We present a high-resolution structure of an a-synuclein fibril, in a form that induces robust pathology in primary neuronal
culture, determined by solid-state NMR spectroscopy and validated by EM and X-ray fiber diffraction. Over 200 unique longrange distance restraints define a consensus structure with common amyloid features including parallel, in-register b-sheets and
hydrophobic-core residues, and with substantial complexity arising from diverse structural features including an intermolecular
salt bridge, a glutamine ladder, close backbone interactions involving small residues, and several steric zippers stabilizing a new
orthogonal Greek-key topology. These characteristics contribute to the robust propagation of this fibril form, as supported by
the structural similarity of early-onset-PD mutants. The structure provides a framework for understanding the interactions of asynuclein with other proteins and small molecules, to aid in PD diagnosis and treatment.This study was supported by the US National Institutes of Health (NIH) (grants R01-GM073770 to C.M.R., P50-NS053488 to V.M.Y.L. and P01-AG002132 to G.S.) and used SSNMR instrumentation procured with the support of grant S10-RR025037 (to C.M.R.) from the NIH National Center for Research Resources (NCRR). M.D.T., A.J.N. and A.M.B. were supported as members of the NIH Molecular Biophysics Training Grant at the University of Illinois at UrbanaChampaign (T32-GM008276), and D.J.C. is supported by grant T32-AG000255
A novel panel of α-synuclein antibodies reveal distinctive staining profiles in synucleinopathies
α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson’s disease from multiple system atrophy
Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Mitochondrial dysfunction : common final pathway in brain aging and Alzheimer's disease : therapeutic aspects
As a fully differentiated organ, our brain is very sensitive to cumulative oxidative damage of proteins, lipids, and DNA occurring during normal aging because of its high energy metabolism and the relative low activity of antioxidative defense mechanisms. As a major consequence, perturbations of energy metabolism including mitochondrial dysfunction, alterations of signaling mechanisms and of gene expression culminate in functional deficits. With the increasing average life span of humans, age-related cognitive disorders such as Alzheimer's disease (AD) are a major health concern in our society. Age-related mitochondrial dysfunction underlies most neurodegenerative diseases, where it is potentiated by disease-specific factors. AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. In this review, we focus on findings in AD animal and cell models indicating that these histopathological alterations induce functional deficits of the respiratory chain complexes and therefore consecutively result in mitochondrial dysfunction and oxidative stress. These parameters lead synergistically with the alterations of the brain aging process to typical signs of neurodegeneration in the later state of the disease, including synaptic dysfunction, loss of synapses and neurites, and finally neuronal loss. We suggest that mitochondrial protection and subsequent reduction of oxidative stress are important targets for prevention and long-term treatment of early stages of AD