A direct role of aberrant neurofilament accumulation in the etiology of human motor neuron diseases, including amyotrophic lateral sclerosis, is suggested by the presence of abnormal accumulations of neurofilaments as an early hallmark of the pathogenic process. Furthermore, forcing increased expression of neurofilament subunits in transgenic mouse models leads to motor neuron dysfunction, albeit without the widespread motor neuron death typical of human disease. We now show that accumulation of a modest level of a point mutant in the smallest neurofilament subunit (NF-L) causes massive, selective degeneration of spinal motor neurons accompanied by abnormal accumulations of neurofilaments and severe neurogenic atrophy of skeletal muscles. As in human disease, sensory neurons show only a modest level of degenerative changes. Thus, neurofilament mutations can cause selective motor neuron death, and neurofilamentous abnormalities may be a common toxic intermediate that significantly contributes to the motor neuron death in human disease.
Bibliographical noteFunding Information:
We thank our colleagues at Johns Hopkins (Drs. Zuoshang Xu, John Griffin, Paul Hoffman, Tom Crawford, and Don Price) for stimulatingdiscussionsand Ms.JanetFolmerforinvaluabletech-nical assistance. Special thanks are also gratefully given to Dr. Nancy Jenkins (National Cancer Institute, Frederick) for help in construction of transgenic mice and to Dr. Samuel Chou (ALS Foundation, San Francisco) for his detailed discussions with us concerning the pathology of human ALS. We would also like to thank Drs. Teepu Siddique (Northwestern University, Chicago), Guy Rouleau (McGill University, Montreal), and Arthur Clark (University of Calgary) for the personal communications. This work has been supported by a grant from the NIH to D. W. C. (NS27036). M. K. L. has been supported by a postdoctoral fellowship from the NIH. D. W. C. is the recipient of a Jacob Javits Neuroscience Investigator Award from the NIH.