Neuronal Intermediate Filaments and Neurodegenerative Diseases

Abstract

Neuronal intermediate filaments (IFs) are major components of the cytoskeleton in neurons and are composed of a family of neuronal IF proteins that include peripherin, α-internexin, and neurofilament triplet proteins (NFTPs), designated NF-L, NF-M, and NF-H for low, medium, and high molecular weight subunits, respectively. NFTPs are determinants of axonal caliber, while α-internexin may play a role in neuronal regeneration and peripherin in proper development of a defined population of sensory neurons. The composition and proper stoichiometry of these proteins are important for IF assembly and transport. Abnormal IF accumulations in neuronal perikarya and proximal axons are pathological hallmarks of many neurodegenerative diseases. Studies of transgenic mouse models as well as identification of NF-H mutations in sporadic amyotrophic lateral sclerosis (ALS) and NF-L mutations in Charcot-Marie-Tooth disease indicate that neuronal IFs have a direct role in pathogenesis of these diseases. Overexpression of individual NFTP subunit or peripherin in transgenic mice causes abnormal accumulation of IFs in motor neurons and motor dysfunction, reminiscent of ALS, whereas overexpression of α-internexin causes Purkinje cell death and motor coordination deficits. Deletion of NF-L or overexpression of NF-H extends the lifespan of transgenic mice expressing mutated Cu/Zn superoxide dismutase (SOD1), suggesting that NFTPs may also contribute to SOD1 mutation-linked ALS. The misaccumulated IFs in neuronal perikarya and proximal axons are disorganized and aberrantly phosphorylated. The kinases and phosphatases that are known to control phosphorylation of NFTPs are deregulated in the disease state. Studies of transgenic mouse models show that axonal transport of neuronal IFs and other cellular components is impaired in the disease state, ultimately leading to neurodegeneration. Formation of disorganized and aberrantly phospohorylated IFs, changes in stoichiometric levels of neuronal IF proteins due to dysregulation of their gene expression, and reduced levels of functional motor proteins may contribute in part to this defective axonal transport. Recent studies raise the possibility that cis-acting and trans-acting determinants of NF-L mRNA stability may also be involved in degeneration of motor neurons. Taken together, these data suggest that abnormal IF accumulations in neurons may not simply be the by-products of neurodegenerative diseases but may instead play a contributory role in pathogenesis of these diseases.