"Prion-like" seeding and propagation of oligomeric protein assemblies in neurodegenerative disorders.

Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation of such proteins in diseased brains is believed to be the end-stage of a stepwise aggregation of misfolded monomers to insoluble cross-β fibrils via a series of differently sized soluble oligomers/protofibrils. Several studies have shown how α-synuclein, amyloid-β, tau and other amyloidogenic proteins can act as nucleating particles and thereby share properties with misfolded forms, or strains, of the prion protein.

Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity.

Protein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation are a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.

Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network.

The Rho guanine nucleotide exchange factor (RGNEF) protein encoded by the gene has been implicated in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Biochemical and pathological studies have shown that RGNEF is a component of the hallmark neuronal cytoplasmic inclusions in ALS-affected neurons. Additionally, a heterozygous mutation in has been identified in a number of familial ALS (fALS) cases that may give rise to one of two truncated variants of the protein.

ALS Yeast Models-Past Success Stories and New Opportunities.

In the past two decades, yeast models have delivered profound insights into basic mechanisms of protein misfolding and the dysfunction of key cellular pathways associated with amyotrophic lateral sclerosis (ALS). Expressing ALS-associated proteins, such as superoxide dismutase (SOD1), TAR DNA binding protein 43 (TDP-43) and Fused in sarcoma (FUS), in yeast recapitulates major hallmarks of ALS pathology, including protein aggregation, mislocalization and cellular toxicity. Results from yeast have consistently been recapitulated in other model systems and even specimens from human patients, thus providing evidence for the power and validity of ALS yeast models.

Yeast as a model to study protein misfolding in aged cells.

Yeast models of neurodegenerative diseases associated with protein misfolding and protein aggregation have given unique insights into the underlying genetic and cellular pathomechanisms. These yeast models recapitulate central aspects of protein misfolding and the ensuing toxicity, such as interference with cellular protein quality control, concentration-dependent formation of insoluble, often amyloid-like aggregates and the associated toxicity. Advanced age is undoubtedly the highest and most common risk factor for most neurodegenerative diseases.

Candida albicans Is Resistant to Polyglutamine Aggregation and Toxicity.

Disruption of protein quality control can be detrimental, having toxic effects on single cell organisms and contributing to neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's in humans. Here, we examined the effects of polyglutamine (polyQ) aggregation in a major fungal pathogen of humans, Candida albicans, with the goal of identifying new approaches to disable this fungus. However, we discovered that expression of polyQ stretches up to 230Q had no effect on C.

Polyglutamine toxicity in yeast uncovers phenotypic variations between different fluorescent protein fusions.

The palette of fluorescent proteins (FPs) available for live-cell imaging contains proteins that strongly differ in their biophysical properties. FPs cannot be assumed to be equivalent and in certain cases could significantly perturb the behavior of fluorescent reporters. We employed Saccharomyces cerevisiae to comprehensively study the impact of FPs on the toxicity of polyglutamine (polyQ) expansion proteins associated with Huntington's disease.

CAG Expansions Are Genetically Stable and Form Nontoxic Aggregates in Cells Lacking Endogenous Polyglutamine Proteins.

Unlabelled: Proteins containing polyglutamine (polyQ) regions are found in almost all eukaryotes, albeit with various frequencies. In humans, proteins such as huntingtin (Htt) with abnormally expanded polyQ regions cause neurodegenerative diseases such as Huntington's disease (HD). To study how the presence of endogenous polyQ aggregation modulates polyQ aggregation and toxicity, we expressed polyQ expanded Htt fragments (polyQ Htt) in Schizosaccharomyces pombe In stark contrast to other unicellular fungi, such as Saccharomyces cerevisiae, S.

A Toolbox for Rapid Quantitative Assessment of Chronological Lifespan and Survival in Saccharomyces cerevisiae.

Saccharomyces cerevisiae is a well-established model organism to study the mechanisms of longevity. One of the two aging paradigms studied in yeast is termed chronological lifespan (CLS). CLS is defined by the amount of time non-dividing yeast cells can survive at stationary phase.