αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson's Disease?

Parkinson's Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that αSynuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and αSynuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and αSynuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and αSynuclein Oligomerization

Emergent Intra-Pair Sex Differences and Organized Behavior in Pair Bonded Prairie Voles (Microtus ochrogaster)

In pair bonding animals, coordinated behavior between partners is required for the pair to accomplish shared goals such as raising young. Despite this, experimental designs rarely assess the behavior of both partners within a bonded pair. Thus, we lack an understanding of the interdependent behavioral dynamics between partners that likely facilitate relationship success. To identify intra-pair behavioral correlates of pair bonding, we used socially monogamous prairie voles (Microtus ochrogaster) and tested both partners using social choice and non-choice tests at short- and long-term pairing timepoints. Females developed a preference for their partner more rapidly than males, with preference driven by different behaviors in each sex. Further, as bonds matured, intra-pair behavioral sex differences and organized behavior emerged—females consistently huddled more with their partner than males did regardless of overall intra-pair affiliation levels. When animals were allowed to freely interact with a partner or a novel vole in sequential free interaction tests, pairs spent more time interacting together than either animal did with a novel vole, consistent with partner preference in the more commonly employed choice test. Total pair interaction in freely moving voles was correlated with female, but not male, behavior. Via a social operant paradigm, we found that pair-bonded females, but not males, are more motivated to access and huddle with their partner than a novel vole. Together, our data indicate that as pair bonds mature, sex differences and organized behavior emerge within pairs, and that these intra-pair behavioral changes are likely organized and driven by the female animal

Contributions of Intrinsically Disordered Regions of Proteins to the Assembly of Ribonucleoprotein Granules

Cells assemble large, non-membrane bound granules of protein and RNA, termed Ri- bonucleoprotein granules (RNP granules), often in response to a wide variety of cellular stresses. This behavior is conserved from yeast to mammals. Some RNP granules ap- pear important in the stress response, while others are important for proper organismal development, and still others for control of RNA degradation and transport. Curiously, proteins found within granules are disproportionately likey to contain Intrinsically Dis- ordered Regions. Here, I show that those disordered regions can often drive higher order assembly in vitro and contribute to granule assembly in vivo. I found that these domains can make it easier for proteins to undergo a process known as Liquid-Liquid Phase Separa- tion in response to changes in ionic strength, wherein the protein of interest self-partitions into a concentrated liquid phase. The droplets that form mimic many of the behaviors of RNP granules in cells, such as recruitment of other IDR-containing proteins, assembly in response to RNA, and rapid exchange of contents with the surrounding medium. I also found that proteins that form these droplets tend to aggregate over time, turning the dynamic droplets into static structures. Further, I identified several limitations to my in vitro model, most importantly the impairment of IDR-based phase separation in the presence of other proteins or cellular lysates. However, I also helped uncover the synergistic relationship between IDRs and the more well studied protein-protein and protein-RNA interactions that are important for granule assembly. I therefore propose an inclusive model of granule assembly which asserts that a wide variety of types of interactions are important, and that it is the sum-total of these interactions that determines whether or not a granule assembles

Intrinsically Disordered Regions Can Contribute Promiscuous Interactions to RNP Granule Assembly

Summary: Eukaryotic cells contain large RNA-protein assemblies referred to as RNP granules, whose assembly is promoted by both traditional protein interactions and intrinsically disordered protein domains. Using RNP granules as an example, we provide evidence for an assembly mechanism of large cellular structures wherein specific protein-protein or protein-RNA interactions act together with promiscuous interactions of intrinsically disordered regions (IDRs). This synergistic assembly mechanism illuminates RNP granule assembly and explains why many components of RNP granules, and other large dynamic assemblies, contain IDRs linked to specific protein-protein or protein-RNA interaction modules. We suggest assemblies based on combinations of specific interactions and promiscuous IDRs are common features of eukaryotic cells