Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability

An Inhibitory Sex Pheromone Tastes Bitter for Drosophila Males

Sexual behavior requires animals to distinguish between the sexes and to respond appropriately to each of them. In Drosophila melanogaster, as in many insects, cuticular hydrocarbons are thought to be involved in sex recognition and in mating behavior, but there is no direct neuronal evidence of their pheromonal effect. Using behavioral and electrophysiological measures of responses to natural and synthetic compounds, we show that Z-7-tricosene, a Drosophila male cuticular hydrocarbon, acts as a sex pheromone and inhibits male-male courtship. These data provide the first direct demonstration that an insect cuticular hydrocarbon is detected as a sex pheromone. Intriguingly, we show that a particular type of gustatory neurons of the labial palps respond both to Z-7-tricosene and to bitter stimuli. Cross-adaptation between Z-7-tricosene and bitter stimuli further indicates that these two very different substances are processed by the same neural pathways. Furthermore, the two substances induced similar behavioral responses both in courtship and feeding tests. We conclude that the inhibitory pheromone tastes bitter to the fly

Peripheral, Central and Behavioral Responses to the Cuticular Pheromone Bouquet in Drosophila melanogaster Males

Pheromonal communication is crucial with regard to mate choice in many animals including insects. Drosophila melanogaster flies produce a pheromonal bouquet with many cuticular hydrocarbons some of which diverge between the sexes and differently affect male courtship behavior. Cuticular pheromones have a relatively high weight and are thought to be — mostly but not only — detected by gustatory contact. However, the response of the peripheral and central gustatory systems to these substances remains poorly explored. We measured the effect induced by pheromonal cuticular mixtures on (i) the electrophysiological response of peripheral gustatory receptor neurons, (ii) the calcium variation in brain centers receiving these gustatory inputs and (iii) the behavioral reaction induced in control males and in mutant desat1 males, which show abnormal pheromone production and perception. While male and female pheromones induced inhibitory-like effects on taste receptor neurons, the contact of male pheromones on male fore-tarsi elicits a long-lasting response of higher intensity in the dedicated gustatory brain center. We found that the behavior of control males was more strongly inhibited by male pheromones than by female pheromones, but this difference disappeared in anosmic males. Mutant desat1 males showed an increased sensitivity of their peripheral gustatory neurons to contact pheromones and a behavioral incapacity to discriminate sex pheromones. Together our data indicate that cuticular hydrocarbons induce long-lasting inhibitory effects on the relevant taste pathway which may interact with the olfactory pathway to modulate pheromonal perception

Dates of Receipt and Acceptance of Articles

To the Editor: There has been a lot of discussion concerning the Journal\u27s policies about publishing articles.1 Also, the general trend toward lengthy time lags involved in submission, receipt, review, revision, acceptance, and publication of articles has been pointed out.2,3 Concerning this, I have a small complaint about the Journal. The articles published in it are not accompanied by the dates of their receipt and acceptance. Such information is provided in a majority of medical journals. This could be of utmost concern to authors interested in being the “first,” especially when an article written by another group on similar

Regulation of vesicular trafficking by Parkinson's disease-associated genes

The regulatory mechanisms that control intracellular vesicular trafficking play important roles in cellular function and viability. Neurons have specific vesicular trafficking systems for synaptic vesicle formation, release and recycling. Synaptic vesicular trafficking impairments induce neuronal dysfunction and physiological and behavioral disorders. Parkinson's disease (PD) is an age-dependent neurodegenerative disorder characterized by dopamine depletion and loss of dopamine neurons in the midbrain. The molecular mechanism responsible for the neurodegeneration that occurs during PD is still not understood; however, recent functional analyses of familial PD causative genes suggest that a number of PD causative genes regulate intracellular vesicular trafficking, including synaptic vesicular dynamics. This review focuses on recent insights regarding the functions of PD causative genes, their relationship with vesicular trafficking and how mutations associated with PD affect vesicular dynamics and neuronal survival

Imbalance of T‐cell Subpopulations Does Not Result in Defective Helper Function in Chronic Lymphocytic Leukemia

The T‐lymphocyte subpopulations identified by the Fc receptors for IgG (TG cells) and IgM (TM cells) in 12 patients with B‐cell chronic lymphocytic leukemia (CLL) were quantitated and studied for functional capabilities in an in vitro assay. The TG cells in patients were elevated in relation to age‐ and sex‐matched normal controls (P \u3c 0.05) resulting in an altered TM/TG ratio of 1.8 ± 0.76 in CLL versus 5.9 ± 3.7 in controls (mean ± SD, P \u3c 0.001). Despite this altered TM/TG ratio, the functional capability of the CLL T cells to regulate the terminal differentiation of B cells was found to be normal as reflected by the mean helper–suppressor score of 0.77 ± 0.13 (±SEM) obtained for both patients and controls. This unimpaired capacity of the T cells from CLL patients to help normal B cells mature into immunoglobulin‐secreting cells indicated that hypogammaglobulinemia and monoclonal serum immunoglobulins in these patients may be a result of either an intrinsic defect in the B lymphocytes or their replacement by a neoplastic clone rather than a defect in the immunoregulatory T cells

Malignant Fibrous Histiocytoma Arising in Previous Surgical Sites.Report of Two Cases

Two patients who developed malignant fibrous histiocytoma in previous surgical sites are reported. One patient developed malignant fibrous histiocytoma in an amputation site, and the other patient developed it in a previous hernioplasty scar. Both patients presented with a mass, clinically interpreted as a subcutaneous abscess. The light microscopic and fine structural features of these tumors are described. A possible causal relationship between previous surgery and malignant fibrous histiocytoma is discussed in view of other reported cases arising in various conditions following chronic reparative reactions. Cancer 53:176‐183, 1984