With dendritic neurofilaments (NFs) and NF reassembly experiments, the phosphorylation of NF-H was found related to development of crossbridges, resulting in alignment of core filaments. When treated with aluminum chloride, rabbits died acutely with tetanic spasm in which NFs were accumulated in neuronal perikarya and proximal axons. Compared with axonal NFs, the NFs accumulated in the perikarya were composed of less-developed cross-bridges and more irregularly aligned core filaments, and their NF-H, although it became phosphorylated, was less phosphorylated. Transgenic mice expressing NF-H-beta-galactosidase protein also showed NF accumulation in the perikarya, which was similar in organization and NF-H phosphorylation to that in aluminum-treated rabbits, but NFs were almost absent from the axonal compartment in these mice that did not show any overt phenotype. Jimpy mutant mice, with dysmyelinated axons and a short lifespan, showed a significant increase in NF density in the axonal compartment. NF-H and its mRNA were drastically enhanced in expression in these mice, whereas enhancement in expression of NF-L and its mRNA was slight. Most increased NF-H, and probably NF-M also, in the axons was of the nonphosphrylated form. NFs that increased in the axons were also constructed of irregularly organized core filaments linked with fewer crossbridges. Another dysmyelinating mutant type of mice, shiverer mice, also showed similar morphological, immunocytochemical, and behavioral characteristics. Taken together, axonal NF accumulation rather than that in the perikarya must be toxic for neurons to provoke axonal degeneration, possibly resulting in reduction of lifespan. In other transgenic mice, however, the elimination of NFs from the axonal compartment seems to make the neuron vulnerable. Nevertheless, because overexpression of NF-H displayed severe neurological disorder while elimination of this protein appeared to be more resistant to some neurotoxic agent, NF-H appears to function as an exacerbation factor when it exists in the neurologically disordered condition. However, as NF-H is provided with a unique carboxy-terminal tail domain that is highly phosphorylated in the axon and because disruption of its gene affected the survival of axons, which did not develop normal axonal caliber, NF-H should play an important role in healthy neurons.