Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and α-synuclein (α-syn) aggregation in Lewy bodies (LB).
• Synapsin III (Syn III) is identified as a key component of LB fibrils, mediating α-syn aggregation and toxicity.
• Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI), treats freezing of gait in PD and attention deficits in ADHD, a condition linked to Syn III and α-syn.

Purpose of the Study:

• To investigate α-syn/Syn III co-deposition and changes in α-syn, Syn III, and dopamine transporter (DAT) levels in a mouse model of PD.
• To analyze the locomotor response to MPH and other MRIs in aging PD model mice.
• To assess MPH's modulation of α-syn/Syn III interaction and its effect on α-syn conformation.

Main Methods:

• Utilized a human C-terminally truncated α-syn transgenic (SYN120 tg) mouse model compared to wild-type and α-syn null littermates.
• Administered MPH, cocaine, and GBR-12935 to assess locomotor activity longitudinally.
• Employed fluorescence resonance energy transfer (FRET) to study drug-induced α-syn/Syn III interactions and in silico modeling.

Main Results:

• Only MPH induced significant locomotor activity in aged SYN120 tg mice with α-syn/Syn III co-aggregates, independent of DAT.
• MPH enhanced α-syn/Syn III interaction in cells with inclusions, with greater effect on truncated α-syn.
• In silico studies suggested MPH stabilizes α-syn conformations, potentially reducing fibrillation and increasing lipid binding.

Conclusions:

• MPH's motor-stimulating effect is potentiated by the presence of α-syn/Syn III co-aggregation.
• MPH may reduce α-syn fibrillation by altering protein conformation.
• Findings have significant implications for the therapeutic management of Parkinson's disease and ADHD.