Extracellular Protein Aggregates Research Articles

Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs

A wide variety of neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates. More recently, the genetic identification of mutations in familial counterparts to the sporadic disorders, leading to the development of in vitro and in vivo model systems, has provided insights into disease pathogenesis. The effect of many of these mutations is the abnormal processing of misfolded proteins that overwhelms the quality-control systems of the cell, resulting in the deposition of protein aggregates in the nucleus, cytosol and/or extracellular space. Further understanding of mechanisms regulating protein processing and aggregation, as well as of the toxic effects of misfolded neurodegenerative disease proteins, will facilitate development of rationally designed therapies to treat and prevent these disorders.

Evidence against increased glycoxidation in patients with Alzheimer's disease

Neuropathological findings of Alzheimer's disease (AD) are intracellular (neurofibrillary tangles) and extracellular (senile plaques) filamentous protein aggregates. Non-enzymatic glycation has been proposed as a primary factor in this pathogenesis, leading to increased insolubility of tau protein and β-amyloid. The aim of our study was to test the hypothesis that increased glycoxidation, i.e. increased levels of oxidized products from non-enzymatic glycation could be found in brains of patients with AD and of aged Down syndrome (DS) subjects with abundant AD-like neuropathological lesions. Frontal cortex specimens were assayed for pentosidine (Pent) and N- ϵ-carboxymethyllysine (CML) by reversed phase high performance liquid chromatographical methods. Pent and CML levels in AD ( n=10; Pent, 35.5±4.84 μmol/g wet-weight tissue; CML, 135.2±5.0 μmol/g wet-weight tissue) were comparable to DS ( n=9; Pent, 36.4±3.21; CML, 133.5±4.7) and controls ( n=10; Pent, 35.2±3.55; CML, 136.9±3.3). We conclude that the results are not compatible with the concept of increased glycoxidation in AD compared to normal aging.

Agrin-Induced Postsynaptic-like Apparatus in Skeletal Muscle Fibersin Vivo

We find that when extrajunctional regions of denervated soleus muscles in adult rats are transfected with cDNA encoding rat agrin isoform Y4Z8, which is normally secreted by motor neurons at adult neuromuscular junctions, the myofibers express and secrete the neural agrin. Muscle fibers in the vicinity of transfection form at their surface specialized areas having extracellular, plasma membrane, and cytoplasmic protein aggregates, narrow and deep plasma membrane infoldings, and an accumulation of myonuclei, all of which are characteristic of the postsynaptic apparatus at neuromuscular junctions. We conclude that at ectopic neuromuscular junctions that form in the extrajunctional region of denervated adult soleus muscles after implantation of a foreign nerve, a single neural-derived factor, agrin, is sufficient not only to cause protein aggregation in the early stages of postsynaptic apparatus formation, as predicted by the agrin hypothesis, but also to bring about changes in conformation of the muscle fiber surface and distribution of organelles which appear as the apparatus reaches maturity.