Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p

The identification of the alpha-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of alpha-synuclein as a component o f Lewy bodies has heralded a new era in the study of Parkinson's disease. W e have identified a large family with Lewy body parkinsonism linked to a no vel locus on chromosome 4p15 that does not have a mutation in the alpha-syn uclein gene. Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular weight a lpha-synuclein-immunoreactive proteins in brain homogenates from brain regi ons with the most marked neuropathology. Distinctive histopathology was rev ealed with alpha-synuclein immunostaining, including pleomorphic Lewy bodie s, synuclein-positive glial inclusions and widespread, severe neuritic dyst rophy. We also discuss the relationship of this familial disorder to a Lewy body disease clinical spectrum, ranging from Parkinson's disease to dement ia with psychosis.