ABSTRACT
Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in ß-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.
Subject(s)
Neurodegenerative Diseases/etiology , Prions/physiology , Age of Onset , Amyloidogenic Proteins/chemistry , Amyloidogenic Proteins/classification , Amyloidogenic Proteins/physiology , Animals , Fungal Proteins/chemistry , Fungal Proteins/classification , Fungal Proteins/physiology , Humans , Inclusion Bodies , Mammals , Models, Molecular , Neurodegenerative Diseases/epidemiology , Neurodegenerative Diseases/genetics , Neurofibrillary Tangles , Peptide Termination Factors/chemistry , Peptide Termination Factors/classification , Peptide Termination Factors/physiology , Plaque, Amyloid , Prion Diseases/etiology , Prion Diseases/genetics , Prions/genetics , Protein Conformation , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/classification , Saccharomyces cerevisiae Proteins/physiology , Synucleins/physiology , Tauopathies/etiology , Tauopathies/genetics , Transcription Factors/chemistry , Transcription Factors/classification , Virulence , mRNA Cleavage and Polyadenylation Factors/chemistry , mRNA Cleavage and Polyadenylation Factors/classification , tau Proteins/genetics , tau Proteins/physiologyABSTRACT
Long-term memory and synaptic plasticity are thought to require the synthesis of new proteins at activated synapses. The CPEB family of RNA binding proteins, including Drosophila Orb2, has been implicated in this process. The precise mechanism by which these molecules regulate memory formation is however poorly understood. We used gene targeting and site-specific transgenesis to specifically modify the endogenous orb2 gene in order to investigate its role in long-term memory formation. We show that the Orb2A and Orb2B isoforms, while both essential, have distinct functions in memory formation. These two isoforms have common glutamine-rich and RNA-binding domains, yet Orb2A uniquely requires the former and Orb2B the latter. We further show that Orb2A induces Orb2 complexes in a manner dependent upon both its glutamine-rich region and neuronal activity. We propose that Orb2B acts as a conventional CPEB to regulate transport and/or translation of specific mRNAs, whereas Orb2A acts in an unconventional manner to form stable Orb2 complexes that are essential for memory to persist.
