Post-translational modifications (PTMs) of proteins are biochemical processes required for cellular functions and signalling that occur in every sub-cellular compartment. Multiple protein PTMs exist, and are established by specific enzymes that can act in basal conditions and upon cellular activity. In the nucleus, histone proteins are subjected to numerous PTMs that together form a histone code that contributes to regulate transcriptional activity and gene expression. Despite their importance however, histone PTMs have remained poorly characterised in most tissues, in particular the brain where they are thought to be required for complex functions such as learning and memory formation. Here, we report the comprehensive identification of histone PTMs, of their combinatorial patterns, and of the rules that govern these patterns in the adult mouse brain. Based on liquid chromatography, electron transfer, and collision-induced dissociation mass spectrometry, we generated a dataset containing a total of 10,646 peptides from H1, H2A, H2B, H3, H4, and variants in the adult brain. 1475 of these peptides carried one or more PTMs, including 141 unique sites and a total of 58 novel sites not described before. We observed that these PTMs are not only classical modifications such as serine/threonine (Ser/Thr) phosphorylation, lysine (Lys) acetylation, and Lys/arginine (Arg) methylation, but also include several atypical modifications such as Ser/Thr acetylation, and Lys butyrylation, crotonylation, and propionylation. Using synthetic peptides, we validated the presence of these atypical novel PTMs in the mouse brain. The application of data-mining algorithms further revealed that histone PTMs occur in specific combinations with different ratios. Overall, the present data newly identify a specific histone code in the mouse brain and reveal its level of complexity, suggesting its potential relevance for higher-order brain functions.

α-Synuclein (α-syn) is a presynaptic protein present at most nerve terminals, but its function remains largely unknown. The familial forms of Parkinson's disease associated with multiplications of the α-syn gene locus indicate that overabundance of this protein might have a detrimental effect on dopaminergic transmission. To investigate this hypothesis, we use adeno-associated viral (AAV) vectors to overexpress human α-syn in the rat substantia nigra. Moderate overexpression of either wild-type (WT) or A30P α-syn differs in the motor phenotypes induced, with only the WT form generating hemiparkinsonian impairments. Wild-type α-syn causes a reduction of dopamine release in the striatum that exceeds the loss of dopaminergic neurons, axonal fibers, and the reduction in total dopamine. At the ultrastructural level, the reduced dopamine release corresponds to a decreased density of dopaminergic vesicles and synaptic contacts in striatal terminals. Interestingly, the membrane-binding-deficient A30P mutant does neither notably reduce dopamine release nor it cause ultrastructural changes in dopaminergic axons, showing that α-syn's membrane-binding properties are critically involved in the presynaptic defects. To further determine if the affinity of the protein for membranes determines the extent of motor defects, we compare three forms of α-syn in conditions leading to pronounced degeneration. While membrane-binding α-syns (wild-type and A53T) induce severe motor impairments, an N-terminal deleted form with attenuated affinity for membranes is inefficient in inducing motor defects. Overall, these results demonstrate that α-syn overabundance is detrimental to dopamine neurotransmission at early stages of the degeneration of nigrostriatal dopaminergic axons.

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Purpose The goal of this study was to investigate the use of spectacles in everyday life after bilateral cataract surgery with a preoperative refractive target of emmetropia in both eyes. In addition, we analyzed the total cost of spectacles and the patientʼs visual satisfaction at least 6 months after surgery. Methods Patients after bilateral cataract surgery with implantation of an aspheric monofocal IOL (Tecnis 1, Johnson & Johnson) with a preoperative refractive target of emmetropia in both eyes and a documented refractive outcome were included in this prospective observational study. In a phone interview ≥ 6 months after surgery, the following items were assessed: type of spectacles purchased and overall cost, type of activity with and duration of spectacle wear, and satisfaction with the visual situation. Results Seventy patients were included in this study. Depending on their postoperative refraction, patients were divided into group A (n = 27) with perfect emmetropia in both eyes (i.e., spherical equivalent [SE] of ≥ − 0.25 D to ≤ + 0.25 D), group B (n = 21) with achieved emmetropia in one eye (i.e., SE of ≥ − 0.25 D to ≤ + 0.25 D) and a myopic refraction in the other eye (< − 0.25 D), and group C (n = 22) with bilateral myopic results (SE of < − 0.25 D). Overall, 84% of patients had purchased new spectacles, mostly varifocals (59%) or reading glasses (24%) at the median cost of 980 Swiss Francs (mean: CHF 912 ± 746). Despite patientsʼ initial reasoning for their lens choice to require reading glasses only, varifocal glasses were worn for more than 50% or all of awake time by 48% of patients in group A, 43% in group B, and 68% in group C. Despite their regular spectacles use, patientsʼ visual satisfaction was very high in all three groups. Conclusions Most patients who achieve perfect bilateral emmetropia after implantation of monofocal aspheric lenses buy varifocal spectacles within 6 months, and more than half of all patients use their varifocal spectacles for more than 50% of their awakening time. The costs for such spectacles are high.