THE NEUROPATHOLOGY OF A CHROMOSOME 17-LINKED AUTOSOMAL-DOMINANT PARKINSONISM AND DEMENTIA (PALLIDO-PONTO-NIGRAL DEGENERATION)

A group of similar autosomal dominant hereditary neurodegenerative dis orders have been linked to chromosome 17 in thirteen kindreds. One of these disorders, known as pallido-ponto-nigral degeneration (PPND), is characterized by extensive degeneration of the globus pallidus and su bstantia nigra as well as accumulation of abnormally phosphorylated ta u proteins. The authors now present comprehensive data on the cellular and molecular pathology of PPND, allowing its classification among ch romosome 17-linked neurodegenerative disorders as well as its classifi cation among sporadic and other familial tauopathies. First, we showed that PPND is characterized by abundant ballooned neurons in neocortic al and subcortical regions as well as by tau-rich inclusions in the cy toplasm of neurons and oligodendroglia morphologically similar to thos e seen in corticobasal degeneration (CBD), but in a distribution patte rn resembling progressive supranuclear palsy (PSP). Second, we demonst rated that antibodies to phosphorylation-independent (Alz50, 133, 303, Tau-2, T-46) as well as phosphorylation-dependent (AT8, PHF-6, 12E8, PHF-1, T3P, pS427) epitopes in human tau proteins stain these glial an d neuronal inclusions as intensely as they stain CBD or PSP inclusions . Third, we probed PPND brain by Western blots using some of the same anti-tau antibodies to reveal 2 tau immunobands with molecular weights of 69 kD and 64 kD in gray and white matter extracts, as reported for both PSP and CBD. Finally, electron microscopy showed that these abno rmal tau proteins formed flat twisted ribbons with a maximum diameter of 20 nanometers (nm) and a periodicity of about 200 nm, resembling th ose reported in CBD. Based on this, we conclude that PPND is a heredit ary neurodegenerative disorder characterized by neuronal and glial tau -rich inclusions formed from aggregated filaments and hyperphosphoryla ted tau proteins and, hence, can be subcategorized into the tauopathy group of chromosome 17-linked neurodegenerative disorders. Further, si nce the morphologic and biochemical lesions of PPND overlap with those seen in sporadic CBD and PSP, we speculate that these disorders share common pathogenetic mechanisms.