Altogether the findings seem to suggest that fibrillar, as well as other types of aSN aggregates, are associated with pathophysiological effects of aSN in vivo . Phosphorylated mono- and di-ubiquitinated aSN forms exist in human brains with a-synucleinopathy suggesting that phosphorylated aSN is targeted to mono- and di-ubiquitination . UCH-L1 and/or Parkin mediated ubiquitination of aSN could control its function, catabolism/stability, localization and interaction with other molecules and levels of toxic protofibrils, although knock-out of UCH-L1 in Thy1-maSN had no effect on aSN metabolism and localization . Ubiquitination in Thy1-maSN transgenic mice was evident along with the other histopathologies in every mouse that we analysed and was restricted to brainstem, cerebellum and spinal cord. This is in contrast to mice over-expressing the human form of aSN showing ubiquitination only sporadically . The amino-acid sequence of human and mouse aSN are very similar and differ only at seven positions. This includes position 53, where in wildtype mouse aSN the amino-acid threonine instead of alanine is present. The human pathogenic mutation A53T hence naturally exists in mouse and thus, cannot account for the difference ZD-1839 EGFR/HER2 inhibitor observed in ubiquitination in mice over-expressing wildtype mouse and human A53T pointmutated aSN. This suggests that rather the six other amino-acid differences between human and mouse that are located downstream of position 53 guide the ubiquitin pathology. In human brains, ubiquitinated structures represent mainly classical Lewy bodies and Lewy neurites . However, the brain areas positive for strong ubiquitination in our mice did not display any enhanced degree of aSN aggregation. This indicates that ubiquitination might not be required for the formation aSN inclusions as described elsewhere . Mice over-expressing murine wildtype aSN showed no early motor deficits aside from minor motor learning impairment. Motor impairments are not obvious until 6 months of age that coincide with a rapid decline in health, resulting in death of the animal. This is in sharp contrast to mice over-expressing human aSN displaying early-onset motor deficits.