Involvement of neurofilaments in motor neuron disease

Abstract

Motor neuron disease is clinically characterized by pro gressive muscle wasting leading to total muscle paraly sis. A long history of pathological study of patients has firmly established that the primary lesion site is in spinal and cortical motor neurons. In addition to the wide spread loss of these neurons, neuronal abnormalities including massive accumulation of neurofilaments in cell bodies and proximal axons have been also widely observed, particularly in the early stages of the disease. To test whether high accumulation of neurofilaments directly contributes to the pathogenic process, trans genic mice that produce high levels of neurofilaments in motor neurons have been generated. These transgenic mice show most of the hallmarks observed in motor neuron disease, including swollen perikarya with eccen trically localized nuclei, proximal axonal swellings, axonal degeneration and severe skeletal muscle atrophy. These data indicate that extensive accumulation of neurofllaments in motor neurons can trigger a neurode generative process and may be a key intermediate in the pathway of pathogenesis leading to neuronal loss.

Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

“…Axonal transport is an energydependent process that is especially crucial to the long axons affected in HSP, which transport molecules and organelles assembled in the neuronal cell body across long distances. Disorganization of the neurofilament network is a common hallmark of toxic neuropathies (36) and of many neurodegenerative diseases, such as amyotrophic lateral sclerosis, giant axonal neuropathy, infantile spinal muscular atrophy, and axonal Charcot-Marie-Tooth disease (37)(38)(39)(40)(41)(42). Axonal inclusions of intermediate filaments have been proposed to "strangulate" the axon by a chronic deficit in transport, thus leading to neurodegeneration (43).…”

Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant

“…Primary antibody specificity was determined by inhibition of binding in the presence of 10 mM 3-nitro-L-tyrosine (Sigma). Neurofilament preparations were immunoblotted with rabbit polyclonal antibodies recognizing glial fibrillary acidic protein (GFAP; Dako), the carboxyl termini of neurofilament light (NF-L) and heavy (NF-H) subunits (23), and monoclonal antibodies to medium (NF-M) subunits (Boehringer Mannheim). Bound primary antibody was detected with 125 I-labeled protein A.…”

Electron tomographic analysis of cytoskeletal cross-bridges in the paranodal region of the node of Ranvier in peripheral nerves

“…For example, missense and splice-site mutations of tau, a protein that stabilizes microtubules, cause aberrant filamentous assembly that is involved with a variety of human cognitive diseases, including Alzheimer's disease, inherited frontotemporal dementia, and Parkinsonism (Garcia and Cleveland, 2001). Disruption of cross-bridging and abnormal accumulation of neurofilaments are pathologic for a series of motor neuron diseases, among which are infantile spinal muscular atrophy, familial and sporadic amyotrophic lateral sclerosis (ALS), and hereditary sensory motor neuropathy Xu et al, 1993). The mechanism of ALS disease is thought to stem from disorganization of neurofilament connectivity that would disrupt the transportation of cargo along the axon (Collard et al, 1995;Fuchs and Cleveland, 1998).…”