Across all kingdoms in the tree of life, calcium (Ca2+) is an essential element used by cells to respond and adapt to constantly changing environments. In multicellular organisms, it plays fundamental roles during fertilization, development and adulthood. The inability of cells to regulate Ca2+ can lead to pathological conditions that ultimately culminate in cell death. One such pathological condition is manifested in Parkinson's disease, the second most common neurological disorder in humans, which is characterized by the aggregation of the protein, α-synuclein. This Review discusses current evidence that implicates Ca2+ in the pathogenesis of Parkinson's disease. Understanding the mechanisms by which Ca2+ signaling contributes to the progression of this disease will be crucial for the development of effective therapies to combat this devastating neurological condition.

Ykt6 is a soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) critically involved in diverse vesicular fusion pathways. While most SNAREs rely on transmembrane domains for their activity, Ykt6 dynamically cycles between the cytosol and membrane-bound compartments where it is active. The mechanism that regulates these transitions and allows Ykt6 to achieve specificity toward vesicular pathways is unknown. Using a Parkinson’s disease (PD) model, we found that Ykt6 is phosphorylated at an evolutionarily conserved site which is regulated by Ca2+ signaling. Through a multidisciplinary approach, we show that phosphorylation triggers a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. In the phosphorylated open form, the spectrum of protein interactions changes, leading to defects in both the secretory and autophagy pathways, enhancing toxicity in PD models. Our studies reveal a mechanism by which Ykt6 conformation and activity are regulated with potential implications for PD.

The nuclear THO and TREX-2 complexes are implicated in several steps of nuclear mRNP biogenesis, including transcription, 3′ end processing and export. In a recent genomic microscopy screen in Saccharomyces cerevisiae for mutants with constitutive stress granules, we identified that absence of THO and TREX-2 complex subunits leads to the accumulation of Pab1-GFP in cytoplasmic foci. We now show that these THO/TREX-2 mutant induced foci ("TT foci") are not stress granules but instead are a mRNP granule containing poly(A) + mRNA, some mRNP components also found in stress granules, as well several proteins involved in mRNA 3 ′ end processing and export not normally seen in stress granules. In addition, TT foci are resistant to cycloheximide-induced disassembly, suggesting the presence of mRNPs impaired for entry into translation. THO mutants also exhibit defects in normal stress granule assembly. Finally, our data also suggest that TT foci are targeted by autophagy. These observations argue that defects in nuclear THO and TREX-2 complexes can affect cytoplasmic mRNP function by producing aberrant mRNPs that are exported to cytosol, where they accumulate in TT foci and ultimately can be cleared by autophagy. This identifies a novel mechanism of quality control for aberrant mRNPs assembled in the nucleus.

Protein translation is a foundational attribute of all living cells. The translation function carried out by the ribosome critically depends on an assortment of protein interaction partners, collectively referred to as the translation machinery. Various studies suggest that the diversification of the translation machinery occurred prior to the last universal common ancestor, yet it is unclear whether the predecessors of the extant translation machinery factors were functionally distinct from their modern counterparts. Here we reconstructed the shared ancestral trajectory and subsequent evolution of essential translation factor GTPases, elongation factor EF-Tu (aEF-1A/eEF-1A), and initiation factor IF2 (aIF5B/eIF5B). Based upon their similar functions and structural homologies, it has been proposed that EF-Tu and IF2 emerged from an ancient common ancestor. We generated the phylogenetic tree of IF2 and EF-Tu proteins and reconstructed ancestral sequences corresponding to the deepest nodes in their shared evolutionary history, including the last common IF2 and EF-Tu ancestor. By identifying the residue and domain substitutions, as well as structural changes along the phylogenetic history, we developed an evolutionary scenario for the origins, divergence and functional refinement of EF-Tu and IF2 proteins. Our analyses suggest that the common ancestor of IF2 and EF-Tu was an IF2-like GTPase protein. Given the central importance of the translation machinery to all cellular life, its earliest evolutionary constraints and trajectories are key to characterizing the universal constraints and capabilities of cellular evolution.

Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a trace amine-associated receptor 1–Orai1–Ca 2+ –calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the monocarboxylase transporter 2–calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halt lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a unique function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.