Overexpression of phosphorylated and truncated α-Synuclein does not trigger Parkinsonian readouts in A53T-SNCA mice.

Parkinson's disease is a multisystem disorder with a prodromal phase marked by non-motor symptoms such as olfactory dysfunction and REM sleep behavior disorder, which may precede classical motor features by several years. Accurately capturing this prodromal-to-motor progression remains a key challenge in preclinical models. This study investigated whether transgenic bacterial artificial chromosome mice expressing human A53T α-Synuclein recapitulate the progression from prodromal to motor stages of Parkinson's disease. Heterozygous A53T-SNCA mice (n = 20) and wild-type controls (n = 21) were longitudinally assessed over 24 months using behavioral, electrophysiological, and neuropathological approaches. EEG-EMG and local field potential recordings were used to evaluate sleep disturbances and neuronal activity, while olfactory and motor function were assessed using behavioral paradigms. A53T-SNCA mice showed transgene dose-dependent overexpression of α-Synuclein monomers with Serine129 phosphorylation and C-terminal truncation across olfactory bulb, striatum, and cortex. However, no higher-molecular-weight α-Synuclein species, indicative of aggregation, were detected. Furthermore, mice did not exhibit olfactory deficits, REM sleep abnormalities, motor impairments, or robust dopaminergic neurodegeneration. In summary, overexpression of modified α-Synuclein monomers was insufficient to drive fibrillar aggregation, neurodegeneration, or (non-) motor symptoms relevant to Parkinson's disease. These findings highlight key limitations of overexpression-based models and suggest that additional drivers are required to recapitulate the pathogenesis.