Prion diseases are infectious neurodegenerative disorders characterised by accumulations of abnor... more Prion diseases are infectious neurodegenerative disorders characterised by accumulations of abnormal prion glycoprotein in affected tissues. Following peripheral exposure, many prion strains replicate upon follicular dendritic cells (FDC) in lymphoid tissues before infecting the brain. An intact splenic marginal zone is important for the efficient delivery of prions to FDC. The marginal zone contains a ring of specific intercellular adhesion molecule-3-grabbing non-integrin related 1 (SIGN-R1)-expressing macrophages. This lectin binds dextran and capsular pneumococcal polysaccharides, and also enhances the clearance of apoptotic cells via interactions with complement components. Since prions are acquired as complement-opsonized complexes we determined the role of SIGN-R1 in disease pathogenesis. We show that transient down-regulation of SIGN-R1 prior to intravenous prion exposure had no effect on the early accumulation of prions upon splenic FDC or their subsequent spread to the brain. Thus, SIGN-R1 expression by marginal zone macrophages is not rate-limiting for peripheral prion disease pathogenesis.
Amyloids are ordered protein aggregates that are typically associated with neurodegenera-tive dis... more Amyloids are ordered protein aggregates that are typically associated with neurodegenera-tive diseases and cognitive impairment. By contrast, the amyloid-like state of the neuronal RNA binding protein Orb2 in Drosophila was recently implicated in memory consolidation, but it remains unclear what features of this functional amyloid-like protein give rise to such diametrically opposed behaviour. Here, using an array of biophysical, cell biological and behavioural assays we have characterized the structural features of Orb2 from the mono-mer to the amyloid state. Surprisingly, we find that Orb2 shares many structural traits with pathological amyloids, including the intermediate toxic oligomeric species, which can be sequestered in vivo in hetero-oligomers by pathological amyloids. However, unlike pathological amyloids, Orb2 rapidly forms amyloids and its toxic intermediates are extremely transient , indicating that kinetic parameters differentiate this functional amyloid from pathological amyloids. We also observed that a well-known anti-amyloidogenic peptide interferes with long-term memory in Drosophila. These results provide structural insights into how the amyloid-like state of the Orb2 protein can stabilize memory and be nontoxic. They also provide insight into how amyloid-based diseases may affect memory processes. Amyloids are ordered protein aggregates typically associated with neurodegenerative diseases , such as Alzheimer disease and Parkinson disease, which usually result in cognitive impairment. However, the amyloid state of the neuronal RNA binding protein Orb2
Prion diseases are infectious neurodegenerative disorders characterised by accumulations of abnor... more Prion diseases are infectious neurodegenerative disorders characterised by accumulations of abnormal prion glycoprotein in affected tissues. Following peripheral exposure, many prion strains replicate upon follicular dendritic cells (FDC) in lymphoid tissues before infecting the brain. An intact splenic marginal zone is important for the efficient delivery of prions to FDC. The marginal zone contains a ring of specific intercellular adhesion molecule-3-grabbing non-integrin related 1 (SIGN-R1)-expressing macrophages. This lectin binds dextran and capsular pneumococcal polysaccharides, and also enhances the clearance of apoptotic cells via interactions with complement components. Since prions are acquired as complement-opsonized complexes we determined the role of SIGN-R1 in disease pathogenesis. We show that transient down-regulation of SIGN-R1 prior to intravenous prion exposure had no effect on the early accumulation of prions upon splenic FDC or their subsequent spread to the brain. Thus, SIGN-R1 expression by marginal zone macrophages is not rate-limiting for peripheral prion disease pathogenesis.
Amyloids are ordered protein aggregates that are typically associated with neurodegenera-tive dis... more Amyloids are ordered protein aggregates that are typically associated with neurodegenera-tive diseases and cognitive impairment. By contrast, the amyloid-like state of the neuronal RNA binding protein Orb2 in Drosophila was recently implicated in memory consolidation, but it remains unclear what features of this functional amyloid-like protein give rise to such diametrically opposed behaviour. Here, using an array of biophysical, cell biological and behavioural assays we have characterized the structural features of Orb2 from the mono-mer to the amyloid state. Surprisingly, we find that Orb2 shares many structural traits with pathological amyloids, including the intermediate toxic oligomeric species, which can be sequestered in vivo in hetero-oligomers by pathological amyloids. However, unlike pathological amyloids, Orb2 rapidly forms amyloids and its toxic intermediates are extremely transient , indicating that kinetic parameters differentiate this functional amyloid from pathological amyloids. We also observed that a well-known anti-amyloidogenic peptide interferes with long-term memory in Drosophila. These results provide structural insights into how the amyloid-like state of the Orb2 protein can stabilize memory and be nontoxic. They also provide insight into how amyloid-based diseases may affect memory processes. Amyloids are ordered protein aggregates typically associated with neurodegenerative diseases , such as Alzheimer disease and Parkinson disease, which usually result in cognitive impairment. However, the amyloid state of the neuronal RNA binding protein Orb2
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Papers by Hamza Kaya