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Volume 17, Number 3, Issue of February 1, 1997 pp. 1064-1074
Copyright ©1997 Society for Neuroscience

Selective Degeneration of Purkinje Cells with Lewy Body-Like Inclusions in Aged NFHLACZ Transgenic Mice

Received Sept. 9, 1996; revised Nov. 11, 1996; accepted Nov. 15, 1996.

Pang-hsien Tu¹, Kathryn A. Robinson¹, Femke de Snoo¹, Joel Eyer², Alan Peterson³, Virginia M.-Y. Lee¹, and John Q. Trojanowski¹

¹ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ² Institut National de la Santé et de la Recherche Médicale Unit 298, 49033 Angers, Cedex 01, France, and ³ Department of Neurology and Neurosurgery, McGill University, Royal Victoria Hospital, Quebec H3A 1A1, Canada

Transgenic (NFHLacZ) mice expressing a fusion protein composed of a truncated high-molecular-weight mouse neurofilament (NF) protein (NFH) fused to -galactosidase (LacZ) develop inclusions in neurons throughout 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 endogenous NF proteins are selectively reduced in NFHLacZ mice. Because these inclusions resemble NF-rich Lewy bodies (LBs) in Parkinson's disease and LB dementia, we asked whether these lesions compromised the viability of affected neurons during aging. We studied hippocampal CA1 neurons, nearly all of which harbored inclusions (type I) devoid of cellular organelles, and cerebellar Purkinje cells, nearly all of which accumulated inclusions (type II) containing numerous entrapped organelles. Purkinje cells with type II inclusions began to degenerate in the NFHLacZ mice at ~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 sequestration of cellular organelles in type II inclusions may isolate and impair the function of these organelles, thereby rendering Purkinje cells selectively vulnerable to degeneration with age as in neurodegenerative diseases of the elderly characterized by accumulation of LBs.

Key words: neurofilament; neurodegeneration; necrosis; phosphorylation; apoptosis; Lewy body; Purkinje cells; Parkinson's disease

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