Relationship between neurodegenerative diseases and neurofilaments accumulated in somata and/or axons

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Abnormal neurofilament (NF) accumulation in neuronal somata and/or axons is seen in some of neurodegenerative diseases, such as amyotrophic lateral sclerosis, in demyelinated diseases, in mice overexpressing exogenous NF gene, and in aged animals including human. The fact that the transgenic mice overexpressing the NF gene show neuronal degeneration suggests that the abnormal NF accumulation is related with the mutation or alteration in the NF genes. To clarify the mechanism of NF accumulation, we made knockout mice devoid of each NF subunit gene and analysed them with biochemical and morphological methods. We also made knockin mice, in which NF-M, NF-H or both genes were replaced to delete their carboxy-terminal tail domains, to know how the absence of crossbridges influence the NF organization or neuronal structure. In all transgenic mice, alterations in structure and/or cytoskeletal organization were detectable predominantly in the axonal compartment. NF-L knockout mice showed expre … More ssions of NF-M and NF-M mRNAs but hardly those of their proteins, resulting in absence of NFs and reduction of axonal calibers, but increase in density of microtubules. NF-M knockout mice showed a reduced expression of NF-L protein, and their NFs were decreased in number and irregular. NF organization was almost unchanged in NF-H knockout mice, in which NF- M protein was increased in amount. Although selective deletion of the NF-M tail had no significant change in NF organization, similar loss of NF-H tail had significant reduction of crossbridges and more compaction of core filaments. Deletion of both tails showed reduction of axonal calibers and significant change in axoplasmic organization, i.e., core filaments were irregular with complete absence of crossbridges, sometimes occupied with membrane-bound organelles, indicating impairment of the axonal transport. There were increases in both size and density of mitochondria when the axonal calibers were reduced. Taken together, abnormal accumulation of NFs in the neurons may be prevented by the NF gene theraphy. Less