Dose-dependent selective suppression of light (NFL) and medium (NFM) but not heavy (NFH) molecular weight neurofilament mRNA levels in acute aluminum neurotoxicity.

We inoculated 5- to 6-week old New Zealand white rabbits intracisternally with either 100, 250, 500, 750, or 1000 micrograms of AlCl3 or 0.9% NaCl and correlated the extent of cervical motor neuron neurofilamentous inclusion formation at 48 h postinoculation with alterations in neurofilament (NF) mRNA levels. RNA was isolated from cervical spinal cord by the guanidine isothiocyanate method and individual RNA samples were normalized for poly(A+) content. Northern blot analysis was performed with cDNA probes for light (NFL), medium (NFM), and heavy (NFH) neurofilament subunit protein or with oligonucleotide probes for alpha-tubulin or actin. No significant alteration in the levels of alpha-tubulin, actin, or NFH mRNA were observed, regardless of the aluminum dose. In contrast, dose-dependent reductions in NFL and NFM mRNA levels occurred in direct proportion to the extent of neurofilamentous inclusion formation. While inoculums of NaCl or 100 or 250 micrograms AlCl3 induced neither inclusion formation or alterations in mRNA levels, both inclusion formation and reductions in the levels of NFL and NFM mRNA occurred thereafter, becoming maximal with inoculums of 1000 micrograms AlCl3. These experiments indicate that intracisternally administered AlCl3 acutely suppresses NFL and NFM mRNA levels without affecting those of NFH. This pattern is in distinct contrast to the uniform reductions of all NF mRNA transcript levels during neurogenesis or following axotomy, indicating a specific effect of aluminum upon steady-state levels of NF mRNA that correlates with the induction of neurofilamentous aggregates.