Livia Breznik Magdalena Daurer ^* Roland Rabl ^* Tina Loeffler ^* Estibaliz Etxeberria-Rekalde ^* Joerg Neddens ^* Stefanie Flunkert Manuela Prokesch ^*

• Scantox Neuro GmbH, Grambach, Austria

BACKGROUND: Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of α-synuclein (α-syn) aggregates. The A53T missense point mutation occurs in autosomal dominant familial PD and has been found to promote the aggregation of α-syn. To investigate the role of the A53T mutation in PD, researchers have developed various mouse models with this mutation. OBJECTIVE: We therefore conducted a comprehensive characterization of the tg(THY1-SNCA*A53T)M53Sud mouse model (hA53Ttg mice) for its motor and pathological features. METHODS: hA53Ttg mice were tested for motor impairments in a series of motor tests at 2, 4 or 6 months of age. Human α-syn and α-syn pSer129, as well as GFAP and Iba1 signal were labelled and quantified in the cortex, hippocampus, and brainstem. Neurofilament light chain (NF-L) levels were measured in the cerebrospinal fluid (CSF) and plasma. Ex vivo analyses were performed at the age of 2, 4, 6 and 10 months. RESULTS: Behavioral tests revealed early muscle weakness and motor impairments that progressed with age. Immunohistochemical analyses demonstrated elevated levels of human α-syn and α-syn pSer129 in all evaluated brain regions. α-syn pSer129 labeling further revealed fiber-like structures in the cortex of older animals. Neuroinflammation was observed in an age-dependent manner. Biochemical evaluation revealed elevated NF-L levels in the plasma and CSF. Overall, our findings highlight the value of hA53Ttg mice in modeling PD-associated pathologies that closely resemble those observed in PD patients. CONCLUSIONS: Our results thus suggest that hA53Ttg mice are a useful tool for studying the underlying mechanisms of PD.