The identity of neuronal cell types is established and maintained by the expression of neuronal genes coding for ion channels, neurotransmitters, and neuropeptides, among others. Some of these genes have been shown to affect lifespan; however, their role in lifespan control remains largely unclear. The Drosophila melanogaster gene Lim3 encodes a transcription factor involved in complicated motor neuron specification networks. We previously identified Lim3 as a candidate gene affecting lifespan. To obtain direct evidence of the involvement of Lim3 in lifespan control, Lim3 overexpression and RNAi knockdown were induced in the nervous system and muscles of Drosophila using the GAL4-UAS binary system. We demonstrated that Lim3 knockdown in the nervous system increased survival at an early age and that Lim3 knockdown in muscles both increased survival at an early age and extended median lifespan, directly establishing the involvement of Lim3 in lifespan control. Lim3 overexpression in nerves and muscles was deleterious and led to lethality and decreased lifespan, respectively. Lim3 misexpression in both nerves and muscles increased locomotion regardless of changes in lifespan, which indicated that the effects of Lim3 on lifespan and locomotion can be uncoupled. Decreased synaptic activity was observed in the neuromuscular junctions of individuals with Lim3 overexpression in muscles, in association with decreased lifespan. However, no changes in NMJ activity were associated with the positive shift in locomotion observed in all misexpression genotypes. Our data suggested that modifications in the microtubule network may be induced by Lim3 misexpression in muscles and cause an increase in locomotion.

Herein we report on the synthesis, structural characterization and photophysical properties of cyclometalated Pt(II) complexes [Pt(N^C)(PPh 2 (C 6 H 4 COOH))Cl] (where N^C ligands are 2-phenylpyridine, (2-benzofuran-3-yl)pyridine, and (2benzo[b]tiophen-3-yl)pyridine) and their conjugates with the histidine-containing RRRRRRRRRRHVLPKVQA peptide. This peptide contains the RHVLPKVQA sequence, which is responsible for antiamyloid activity, and the Arg9 RRRRRRRRR domain, which shows improved translocation through cell membranes. The chemistry underpinning the conjugation is regioselective complexation between Pt(II) complexes and histidine residue in the peptide. The prepared conjugates have been characterized using high-resolution mass spectrometry and NMR spectroscopy. It was shown that the conjugates are easily soluble in aqueous media and display emission band profiles essentially similar to those of the starting complexes but considerably higher luminescence quantum yield and much longer phosphorescence lifetime. MTT assay on HeLa cell culture revealed no cytotoxicity up to 10 μM after 24 h of incubation. Ex vivo and in vivo neuroimaging experiments on both wild and amyloid peptide expressing strains of Drosophila melanogaster revealed that the conjugates penetrate the blood-brain barrier and are evenly distributed throughout the brain independently of the strain used.

Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese (sws)—the evolutionarily conserved ortholog of human NTE/PNPLA6—in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay.