MPTP induces intranuclear rodlet formation in midbrain dopaminergic neurons

Abstract

Neuronal intranuclear rodlets (INRs; rodlets of Roncoroni) have been known to neuroanatomists since the turn of the century. However, the functional and/or pathological significance of these structures has remained enigmatic. We recently demonstrated that these structures are immunoreactive for class III β tubulin and for glucocorticoid receptor. Moreover, they are markedly reduced in the temporal cortex of patients with Alzheimer's disease relative to age-matched controls and those with dementia with Lewy bodies, thereby implicating these structures in neurodegenerative disease pathogenesis. The present report represents an experimental pilot study to investigate the possible involvement of INRs in Parkinson's disease (PD). Specifically, we demonstrate significantly increased INRs in dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area in mice treated with the selective catecholaminergic neurotoxin MPTP, relative to saline-treated controls. We have hypothesized that INRs represent an intranuclear sequestrum of monomeric β-tubulin and that their alteration in neurodegeneration may reflect disrupted or abnormal microtubule dynamics. We propose that the increased formation of INRs is related to the demonstrated ability of MPTP to cause microtubule disruption. Because tubulin has also been implicated in the pathogenesis of human PD, it is possible that the results of this study will have important implications for this most common neurodegenerative movement disorder.