Overexpression of alpha-internexin causes abnormal neurofilamentous accumulations and motor coordination deficits in transgenic mice.

alpha-Internexin is the first neuronal intermediate filament (IF) protein expressed in postmitotic neurons of the developing nervous system. In the adult, its expression is restricted to mature neurons in the CNS. To study the potential role of alpha-internexin in neurodegeneration, we have generated transgenic mice that overexpress rat alpha-internexin. The total levels of alpha-internexin expressed in the hemizygous and homozygous transgenic mice were approximately 2 and approximately 3 times the normal level, respectively. Overexpression of alpha-internexin resulted in the formation of cerebellar torpedoes as early as 1 month of age. These torpedoes are abnormal swellings of Purkinje cell axons that are usually seen in neurodegenerative diseases involving the cerebellum. EM studies showed accumulations of high levels of IFs and abnormal organelles in the torpedoes and soma of Purkinje cells, as well as in the large pyramidal neurons of the neocortex and in the ventral anterior and posteromedial nuclei of the thalamus. Behavioral tests demonstrate that these mice have a deficit in motor coordination as early as 3 months of age, consistent with the morphological neuronal changes. Our data further demonstrate that the neurofilamentous inclusions also lead to progressive loss of neurons in the aged transgenic mice. The motor coordination deficit and the loss of neurons are transgene dosage-dependent. These data yield direct evidence that high levels of misaccumulated neuronal IFs lead to neuronal dysfunction, progressive neurodegeneration, and ultimate loss of neurons. Moreover, the degrees of neuronal dysfunction and degeneration are proportional to the levels of misaccumulated neuronal IFs.