Misfolded proteinase K–resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human α-synucleinopathies

The pathological modifications of -synuclein (S) in Parkinson disease and related diseases are poorly understood. We have detected misfolded S in situ based on the proteinase K resistance (PK resistance) of S fibrils, and using specific antibodies against S129-phosphorylated S as well as oxidized S. Unexpectedly massive neuritic pathology was found in affected human brain regions, in addition to classical S pathology. PK resistance and abnormal phosphorylation of S developed with increasing age in (Thy1)-h[A30P] S transgenic mice, concomitant with formation of argyrophilic, thioflavin S-positive, and electron-dense inclusions that were occasionally ubiquitinated. S pathology in the transgenic mice was predominantly in the brainstem and spinal cord. Astrogliosis was found in these heavily affected tissues. Homozygous mice showed the same pathology approximately one year earlier. The transgenic mice showed a progressive deterioration of locomotor function. Thus, misfolding and hyperphosphorylation of S may cause dysfunction of affected brain regions.