SELECTIVE DEGENERATION OF PURKINJE-CELLS WITH LEWY BODY-LIKE INCLUSIONS IN AGED NFHLACZ TRANSGENIC MICE

Transgenic (NFHLacZ) mice expressing a fusion protein composed of a tr uncated high-molecular-weight mouse neurofilament (NF) protein (NFH) f used to beta-galactosidase (LacZ) develop inclusions in neurons throug hout the CNS. These inclusions persist from birth to advanced age and contain massive filamentous aggregates including all three endogenous NF proteins and the NFHLacZ fusion protein. Further, the levels of end ogenous NF proteins are selectively reduced in NFHLacZ mice. Because t hese inclusions resemble NF-rich Lewy bodies (LBs) in Parkinson's dise ase and LB dementia, we asked whether these lesions compromised the vi ability of affected neurons during aging. We studied hippocampal CA1 n eurons, nearly all of which harbored inclusions (type I) devoid of cel lular organelles, and cerebellar Purkinje cells, nearly all of which a ccumulated inclusions (type II) containing numerous entrapped organell es. Purkinje cells with type II inclusions began to degenerate in the NFHLacZ mice at similar to 1 year of age, and most were eliminated by 18 months of age. In contrast, there was no significant loss of type I inclusion-bearing CA1 neurons with age. These data suggest that the s equestration of cellular organelles in type II inclusions may isolate and impair the function of these organelles, thereby rendering Purkinj e cells selectively vulnerable to degeneration with age as in neurodeg enerative diseases of the elderly characterized by accumulation of LBs .