4-Phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein-C.

Mutations in the SFTPC gene, encoding surfactant protein-C (SP-C), are associated with interstitial lung disease (ILD). Knowledge of the intracellular fate of mutant SP-C is essential in the design of therapies to correct trafficking/processing of the proprotein, and to prevent the formation of cytotoxic aggregates. We assessed the potential of a chemical chaperone to correct the trafficking and processing of three disease-associated mutant SP-C proteins. HEK293 cells were stably transfected with wild-type (SP-C(WT)) or mutant (SP-C(L188Q), SP-C(Δexon4), or SP-C(I73T)) SP-C, and cell lines with a similar expression of SP-C mRNA were identified. The effects of the chemical chaperone 4-phenylbutyric acid (PBA) and lysosomotropic drugs on intracellular trafficking to the endolysosomal pathway and the subsequent conversion of SP-C proprotein to mature peptide were assessed. Despite comparable SP-C mRNA expression, proprotein concentrations varied greatly: SP-C(I73T) was more abundant than SP-C(WT) and was localized to the cell surface, whereas SP-C(Δexon4) was barely detectable. In contrast, SP-C(L188Q) and SP-C(WT) proprotein concentrations were comparable, and a small amount of SP-C(L188Q) was localized to the endolysosomal pathway. PBA treatment restored the trafficking and processing of SP-C(L188Q) to SP-C(WT) concentrations, but did not correct the mistrafficking of SP-C(I73T) or rescue SP-C(Δexon4). PBA treatment also promoted the aggregation of SP-C proproteins, including SP-C(L188Q). This study provides proof of the principle that a chemical chaperone can correct the mistrafficking and processing of a disease-associated mutant SP-C proprotein.

Twenty-eight retinas but only twelve eyes: an anatomical analysis of the larval visual system of the diving beetle Thermonectus marmoratus (Coleoptera: Dytiscidae).

The larvae of the sunburst diving beetle, Thermonectus marmoratus (Coleoptera: Dytiscidae), are highly efficient visually guided predators. Their visual system consists of a cluster of six stemmata and one eye patch on each side of the head capsule. Histological investigations show that the organization of individual stemmata differs strongly from any eye that has previously been described. Based on general morphology, ultrastructural data, and the presence of actin-rich areas that are typical for rhabdoms, we find that each eye is characterized by several retinas. The most dorsal eye on each side is relatively long and tubular, and we have identified three spatially distinct areas with retinula cells: 1) a band of two rows of rhabdoms along the medial side of the eye tube; 2) a flattened cone-shaped region towards the bottom of the tube that is formed by the rhabdoms of retinula cells that are oriented perpendicular to the light path; and 3) two horizontal rows of long rhabdoms parallel to the light path at the base of the tube. A second large eye is organized similarly but lacks the medial band. The remaining four eyes are nearly spherical and each has two distinct retinas. The 12 eyes hence account for a total of 26 retinas, and two further retinas are present in eye patches lacking lenses. Our anatomical findings suggest that this is an example of a visual system in which specific visual tasks are distributed among the eyes, and which relies on a variety of highly specialized retinas.