title: Neurofilament dynamics and involvement in neurological disorders.
abstract: Neurons are extremely polarised cells in which the cytoskeleton, composed of microtubules, microfilaments and neurofilaments, plays a crucial role in maintaining structure and function. Neurofilaments, the 10-nm intermediate filaments of neurons, provide structure and mechanoresistance but also provide a scaffolding for the organization of the nucleus and organelles such as mitochondria and ER. Disruption of neurofilament organization and expression or metabolism of neurofilament proteins is characteristic of certain neurological syndromes including Amyotrophic Lateral Sclerosis, Charcot-Marie-Tooth sensorimotor neuropathies and Giant Axonal Neuropathy. Microfluorometric live imaging techniques have been instrumental in revealing the dynamics of neurofilament assembly and transport and their functions in organizing intracellular organelle networks. The insolubility of neurofilament proteins has limited identifying interactors by conventional biochemical techniques but yeast two-hybrid experiments have revealed new roles for oligomeric, nonfilamentous structures including vesicular trafficking. Although having long half-lives, new evidence points to degradation of subunits by the ubiquitin-proteasome system as a mechanism of normal turnover. Although certain E3-ligases ubiquitinating neurofilament proteins have been identified, the overall process of neurofilament degradation is not well understood. We review these mechanisms of neurofilament homeostasis and abnormalities in motor neuron and peripheral nerve disorders. Much remains to discover about the disruption of processes that leads to their pathological aggregation and accumulation and the relevance to pathogenesis. Understanding these mechanisms is crucial for identifying novel therapeutic strategies.
authors.affiliation: Department of Neurology/Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada, benoit.gentil@mcgill.ca.
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Gentil
authors.forename: Michael
authors.initials: M
authors.lastname: Tibshirani
authors.forename: Heather D
authors.initials: HD
authors.lastname: Durham
mesh_terms: D000818:Animals; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism*; D009422:Nervous System Diseases / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D009928:Organ Specificity