119 research outputs found
The RNA face of phase separation
No full textRNA regulates the formation, identity, and localization of phase-separated granules</jats:p
Characterization of C9orf72 function in autophagy and RNA metabolism
Full text linkAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating neurodegenerative disorders that share clinical, pathological, and genetic features. The most common inheritable cause of ALS and FTD disorders is a hexanucleotide G4C2 repeat expansion within the non-coding region of the C9orf72 gene. Pathogenesis of C9orf72-mediated ALS/FTD is associated with both loss- and gain-of-function mechanisms involving three distinct disease factors. First, bidirectional transcription of the repeat expansion leads to the generation of repeat-containing sense and antisense RNAs. These repeat-RNAs are suggested to form RNA foci and sequester RNA-binding proteins eventually contributing to neurotoxicity. Second, non-conventional translation of repeat-RNAs in all six reading frames generates five distinct dipeptide repeat (DPR) proteins. DPR proteins disturb cellular homeostasis by affecting multiple cellular processes such as nucleocytoplasmic transport and protein translation. Finally, the repeat expansion causes a decrease in C9orf72 transcript and protein levels. C9orf72 protein is an important regulator of the autophagy-related vesicular pathway and the inflammatory response pathway, and its loss leads to their dysregulation. Toxicity due to repeat-RNAs and DPR proteins points towards the presence of gain-of-function mechanisms while haploinsufficiency of C9orf72 protein suggests a loss-of-function disease mechanism. However, the precise molecular and cellular changes caused by the individual and combinatorial expression of these three disease factors and how they contribute to disease pathogenesis remain elusive.
This thesis is aimed to further the understanding of the biochemical and cellular functions of the C9orf72 protein and to disentangle the isolated and combinatorial effects on cellular physiology that is caused by the expression of repeat-RNAs, DPR proteins, and the loss of C9orf72 protein. Single-particle cryo-electron microscopy was used to determine the structure of the C9orf72-SMCR8 complex. The structure shed light on the multifaceted role of the C9orf72 complex and how it might act as a binding platform for protein-protein interactions. Furthermore, a cellular model system was generated that allows the controlled expression of repeat-RNAs and DPR proteins in order to study their spatiotemporal dynamics in the presence and absence of the C9orf72 protein. Moreover, this system is used to systematically characterize individual and combinatorial effects of the three disease factors on RNA and protein metabolism. Therefore, the model system presented in this study is a valuable addition to study the cellular alterations caused by disease factors implicated in C9orf72-mediated ALS/FTD disease
Biological Spectrum of Amyotrophic Lateral Sclerosis Prions
Full text linkAmyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis. Importantly, these assemblies serve as the foci of protein misfolding and mature into insoluble structures, which further recruit native proteins, turning them into misfolded forms. This self-perpetuating mechanism is a twisted version of classical prion replication that leads to amplification of pathological protein complexes that spread throughout the neuraxis, offering a pathogenic principle that underlies the rapid disease progression that characterizes ALS and FTLD
The Seeds of Neurodegeneration: Prion-like Spreading in ALS
No full textMisfolded proteins accumulating in several neurodegenerative diseases (including Alzheimer, Parkinson, and Huntington diseases) can cause aggregation of their native counterparts through a mechanism similar to the infectious prion protein's induction of a pathogenic conformation onto its cellular isoform. Evidence for such a prion-like mechanism has now spread to the main misfolded proteins, SOD1 and TDP-43, implicated in amyotrophic lateral sclerosis (ALS). The major neurodegenerative diseases may therefore have mechanistic parallels for non-cell-autonomous spread of disease within the nervous system
Removal of Extracellular Human Amyloid Beta Aggregation through Metalloproteases and remodelled Extracellular Matrix in C. elegans
No full textFrom nucleation to widespread propagation: A prion-like concept for ALS
No full textAbstractPropagation of pathological protein assemblies via a prion-like mechanism has been suggested to drive neurodegenerative diseases, such as Parkinson's and Alzheimer's. Recently, amyotrophic lateral sclerosis (ALS)-linked proteins, such as SOD1, TDP-43 and FUS were shown to follow self-perpetuating seeded aggregation, thereby adding ALS to the group of prion-like disorders. The cell-to-cell spread of these pathological protein assemblies and their pathogenic mechanism is poorly understood. However, as ALS is a non-cell autonomous disease and pathology in glial cells was shown to contribute to motor neuron damage, spreading mechanisms are likely to underlie disease progression via the interplay between affected neurons and their neighboring glial cells
Mammalian prion biology: one century of evolving concepts.
Full text linkPrions have been responsible for an entire century of tragic episodes. Fifty years ago, kuru decimated the population of Papua New Guinea. Then, iatrogenic transmission of prions caused more than 250 cases of Creutzfeldt-Jakob disease. More recently, transmission of bovine spongiform encephalopathy to humans caused a widespread health scare. On the other hand, the biology of prions represents a fascinating and poorly understood phenomenon, which may account for more than just diseases and may represent a fundamental mechanism of crosstalk between proteins. The two decades since Stanley Prusiner's formulation of the protein-only hypothesis have witnessed spectacular advances, and yet some of the most basic questions in prion science have remained unanswered
- …
