Taken together, the histological and biochemical analyses revealed insoluble, non-fibrillar aggregates in Thy1- maSN mouse brains. Isoelectric focusing Western blotting using several antibodies were performed to characterize the aSN isoforms expressed in the brain of Thy1-maSN mice . We found a novel aSN isoform specific to colliculus and brainstem, the two regions with extensive ubiquitin pathology . Importantly the novel P-Ser129aSN isoform is not detected using aSN antibodies targeting the C-terminus and additionally not present in previously characterized mouse lines expressing haSN . Summarizing the expression of maSN isoforms in mice showed pronounced ubiquitin immunopathology in spinal cord including a novel aSN isoform. Additionally, we observed a strong aSN pathology in the spinal cord accompanied with axonal degeneration. These findings were followed by signs of presynaptic degeneration with reduced neurofilament staining in neuromuscular junction synapses. Interestingly, hippocampal neurons showed strong aSN accumulation but no ubiquitination in contrast to spinal cord motor neurons. CUDC-907 HDAC inhibitor Furthermore, we showed that few neurons in the cortex display an intriguing staining pattern of ubiquitin and phosphorylated maSN, suggesting that these posttranslational modifications play a role in trafficking and localization of aSN. Transgenic animals are considered excellent preclinical models to study a-synuclein disease pathophysiology and test therapeutic strategies. Here we show that wildtype murine aSN can induce pathological changes in mouse brain closely resembling those observed in post-mortem human PD and DLB brains. These transgenic mice are very similar to those over-expressing human wildtype or the familial PD point-mutated A53T aSN . Van der Putten et al. used the same Thy1 promoter to drive comparable aSN levels in similar brain regions compared to our Thy1-maSN transgenic mice. This is very intriguing since for the first time we show that murine aSN as well as human aSN can be pathogenic in neurons in vivo. Interestingly, profound neuropathological changes could be detected solely in spinal cord, brainstem and cerebellum .