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

Abstract

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.

Silencing Parkinson’s risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability

“…We additionally performed immunohistochemistry to ask whether LT Rit2 KD either 1) deleteriously affected DAergic terminals in the DS, or 2) impacted pSer129-Syn aggregation, which is a hallmark of PD. Both males and females exhibited a gross loss of TH+ Article methylphenidate (Ritalin), may have therapeutic potential in PD 37,38 . We asked whether such pharmacological intervention could rescue the motor deficits observed on the rotarod due to Rit2 silencing.…”

Navigating the Frontiers of Machine Learning in Neurodegenerative Disease Therapeutics

“…DeepSite is a deep CNN trained on over 7000 protein structures curated from a publicly available annotated database called sc-PDB [ 58 ], which comprises binding sites characterized from protein structures found in the Protein Data Bank [ 59 ]. Recently, DeepSite analysis revealed allosteric binding motifs in a neuronal protein known as Synapsin III (Syn III) and highlighted the structural interaction between Syn III and methylphenidate, a monoamine reuptake inhibitor used for treating attention deficit hyperactivity disorder [ 60 ]. Syn III is a member of the synapsin protein family, a group of evolutionarily conserved phospho-proteins crucial for regulating synaptic transmitter release and facilitating neuronal communication, and has been recently been associated with the aggregated α-synuclein found in PD and dementia with Lewy bodies (DLB) [ 61 ].…”

Acetylated α-Tubulin and α-Synuclein: Physiological Interplay and Contribution to α-Synuclein Oligomerization

“…α-synuclein aggregation is a multi-step process where, at the early stage, α-synuclein monomers join into small aggregates called oligomers [36]. To test the impact of α-tubulin acetylation on α-synuclein oligomerization, we used the selective HDAC6 inhibitor Tubacin to induce α-tubulin acetylation in a neuroblastoma SK-N-SH cell line overexpressing human wildtype α-synuclein (SK-N-SH Syn + , Figure S5, [37,38]). We evaluated α-synuclein aggregation with: (i) biochemical assays (western blotting analyses of differential soluble extracts); and (ii) the α-Synuclein PLA (AS-PLA) technique, which allows for oligomer detection and quantification in human tissues [39][40][41].…”