Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

Parkinson’s disease (PD) is the most common neurodegenerative disorder with motor symptoms. The neuropathological alterations characterizing the brain of patients with PD include the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies (LB), intraneuronal inclusions that are mainly composed of alpha-synuclein (α-Syn) fibrils. The accumulation of α-Syn in insoluble aggregates is a main neuropathological feature in PD and in other neurodegenerative diseases, including LB dementia (LBD) and multiple system atrophy (MSA), which are therefore defined as synucleinopathies. Compelling evidence supports that α-Syn post translational modifications (PTMs) such as phosphorylation, nitration, acetylation, O-GlcNAcylation, glycation, SUMOylation, ubiquitination and C-terminal cleavage, play important roles in the modulation α-Syn aggregation, solubility, turnover and membrane binding. In particular, PTMs can impact on α-Syn conformational state, thus supporting that their modulation can in turn affect α-Syn aggregation and its ability to seed further soluble α-Syn fibrillation. This review focuses on the importance of α-Syn PTMs in PD pathophysiology but also aims at highlighting their general relevance as possible biomarkers and, more importantly, as innovative therapeutic targets for synucleinopathies. In addition, we call attention to the multiple challenges that we still need to face to enable the development of novel therapeutic approaches modulating α-Syn PTMs

Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson’s Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice

Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy

An updated reappraisal of synapsins: structure, function and role in neurological and psychiatric disorders

Synapsins (Syns) are phosphoproteins strongly involved in neuronal development and neurotransmitter release. Three distinct genes SYN1, SYN2 and SYN3, with elevated evolutionary conservation, have been described to encode for Synapsin I, Synapsin II and Synapsin III, respectively. Syns display a series of common features, but also exhibit distinctive localization, expression pattern, post-translational modifications (PTM). These characteristics enable their interaction with other synaptic proteins, membranes and cytoskeletal components, which is essential for the proper execution of their multiple functions in neuronal cells. These include the control of synapse formation and growth, neuron maturation and renewal, as well as synaptic vesicle mobilization, docking, fusion, recycling. Perturbations in the balanced expression of Syns, alterations of their PTM, mutations and polymorphisms of their encoding genes induce severe dysregulations in brain networks functions leading to the onset of psychiatric or neurological disorders. This review presents what we have learned since the discovery of Syn I in 1977, providing the state of the art on Syns structure, function, physiology and involvement in central nervous system disorders

Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson's disease-like phenotype

Fibrillary aggregated α-synuclein (α-syn) deposition in Lewy bodies (LB) characterizes Parkinson's disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with α-syn to regulate dopamine (DA) release and can be found in the insoluble α-syn fibrils composing LB. Moreover, we showed that α-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human α-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates α-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human α-syn transgenic mice at PD-like stage with advanced α-syn aggregation and overt striatal synaptic failure, we could lower α-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates α-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD

600 MW MARS Nuclear Power Plant

The design of MARS (Multipurpose Advanced “inherently” Safe Reactor) plant started in 1983 at the Department of Nuclear Engineering and Energy Conversion of the University of Rome "La Sapienza", with the aim of proposing a new concept of fission-type nuclear plant to be used for a wide range of applications, including desalination and district heating. The possibility of utilization of the plant in high-density population areas or in developing areas was the main reason for the search for improved safety requirements: the plant had to be simple, with an easy-to-understand and incontrovertible capacity to avoid any radiological hazards to the population. Typically, the safety approach had to be a clearly understandable, deterministic one. The design was focused on a nuclear power generation capacity of 600 MWth, corresponding to about 170 Mwe in the case of only electrical production, with a modular solution to satisfy progressively increasing power requirements