The insect neuropeptides CCHamide-1 and -2 are recently discovered peptides that probably occur in all arthropods. Here, we used immunocytochemistry, in situ hybridization, and quantitative PCR (qPCR), to localize the two peptides in the fruitfly Drosophila melanogaster. We found that CCHamide-1 and -2 were localized in endocrine cells of the midgut of larvae and adult flies. These endocrine cells had the appearance of sensory cells, projecting processes close to or into the gut lumen. In addition, CCHamide-2 was also localized in about forty neurons in the brain hemispheres and ventral nerve cord of larvae. Using qPCR we found high expression of the CCHamide-2 gene in the larval gut and very low expression of its receptor gene, while in the larval brain we found low expression of CCHamide-2 and very high expression of its receptor. These expression patterns suggest the following model: Endocrine CCHamide-2 cells in the gut sense the quality of food components in the gut lumen and transmit this information to the brain by releasing CCHamide-2 into the circulation; subsequently, after binding to its brain receptors, CCHamides-2 induces an altered feeding behavior in the animal and possibly other homeostatic adaptations.

Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages different subtypes of multiple system atrophy are distinguished by their predominant parkinsonian or cerebellar symptoms reflecting the heterogeneous nature of the disease. The pathognomonic feature of multiple system atrophy is the presence of ɑ-synuclein (ɑSyn) protein deposits in oligodendroglial cells. ɑSyn can assemble in specific cellular or disease environments and form ɑSyn strains with unique structural features but the ability of ɑSyn strains to propagate in oligodendrocytes remains elusive. More recently, it was shown that multiple multiple system atrophy strains with related conformations exist in the brain of patients. Here, we investigated if different ɑSyn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant ɑSyn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that ɑSyn protein strains determine disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. ɑSyn strains significantly impact disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of ɑSyn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagate oligodendroglial inclusions that are structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions in multiple system atrophy patient brain. This study therefore shows that the multiple system atrophy phenotype is governed by both the ɑSyn strain nature and the host environment and that by injecting ɑSyn strains in a multiple system atrophy animal model a more comprehensive phenotype can be established.

Aggregation of alpha-synuclein (α-SYN) is the pathological hallmark of several diseases named synucleinopathies, including Parkinson’s disease (PD), which is the most common neurodegenerative motor disorder. Alpha-SYN has been linked to synaptic function both in physiological and pathological conditions. However, the exact link between neuronal activity, α-SYN toxicity and disease progression in PD is not clear. In this study, we aimed to investigate the effect of chronic neuromodulation in an α-SYN-based rat model for PD using chemogenetics. To do this, we expressed excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) combined with mutant A53T α-SYN, using two different recombinant adeno-associated viral (rAAV) vectors (serotypes 2/7 and 2/8) in rat substantia nigra (SN) and investigated the effect on motor behavior, synapses and neuropathology. We found that chronic neuromodulation aggravates motor deficits induced by α-SYN, without altering dopaminergic neurodegeneration. In addition, neuronal activation led to changes in post-translational modification and subcellular localization of α-SYN, linking neuronal activity to the pathophysiological role of α-SYN in PD.