Accumulation of Phosphorylated Neurofilaments in Anterior Horn Motoneurons of Amyotrophic Lateral Sclerosis Patients

Abstract

Perikaryal collections of intermediate filaments have been described in the anterior horn motoneurons of patients with amyotrophic lateral sclerosis (ALS), but these inclusions have generally been considered rare and mainly associated with the familial form of ALS. Using the monoclonal antibody NF2F11, which recognizes phosphorylated neurofilament epitopes, we showed that focal collections of neurofilaments in anterior horn motoneurons were a characteristic finding in sporadic as well as in familial ALS; they were present in seven of nine ALS patients, but in none of nine control spinal cords. These neurofilamentous collections are not cross-reactive with antibodies directed against paired helical filaments and the microtubule associated protein tau. In addition, diffuse staining for phosphorylated neurofilament epitopes in chromatolytic anterior horn perikarya was significantly more frequent in ALS patients than in controls.

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

“…Aberrant accumulation of pNF in axonal swellings and somas has been a hallmark of axonal transport disruption in neurodegenerative diseases (Manetto et al, 1988;Munoz et al, 1988;Mizusawa et al, 1989;Sobue et al, 1990;Rouleau et al, 1996;Stokin et al, 2005). Because phosphorylation of neurofilaments has been shown to de- crease active transport of neurofilaments through retinal axons (Jung and Shea, 1999), it is possible that excess pNF within intraocular axons may itself cause progressive declines in RGC gene expression and retrograde transport.…”

Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice

“…The axonal atrophy and loss were not associated with a significant change in neuronal density in the anterior horn of the spinal cord, suggesting that axons had degenerated in a number of these neurons but that their cell bodies were still present. This hypothesis is supported by the accumulation of phosphorylated neurofilaments in perikarya of spinal cord motor neurons in Tg30tau mice, an event known to be associated with a variety of axonal insults, including axonal transection 62,63 and several neurodegenerative diseases, 64 such as classic amyotrophic lateral sclerosis, 65 Guam amyotrophic lateral sclerosis/parkinsonismdementia complex 48 and transgenic models. 66 Axonal spheroids were numerous in Tg30tau mice and appeared even earlier than NFTs.…”

“…Segregation of cytoplasmic organelles by inclusions in spinal motor neurons, axonal spheroids, and accumulation of neurofilaments are all indicative of disturbances of axonal transport that would be the primary mechanism leading to early deficits in axonal growth and to later axonal degeneration in Tg30tau mice. Disturbance of axonal transports is thought to be a pathogenic mechanism in a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis 65 and early stages of AD. 69 Additional early pathologies might also play a role in disease onset, eg, synapse loss as reported recently in a mutant tau model.…”

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

“…However, the proteins identified so far can include ubiquitin (Leigh et al, 1991;Murayama et al, 1989), Cu/Zn superoxide dismutase 1 (SOD1) (Shibata et al, 1994(Shibata et al, , 1996, peripherin (He and Hays, 2004), Dorfin (a RING-finger type E3 ubiquitin ligase) (Niwa et al, 2002), and more rarely synuclein (Sone et al, 2005). Various studies conducted in ALS postmortem tissue in the early nineties found accumulations of intermediate filament proteins (hyperphosphorylated neurofilament subunits and peripherin) in hyaline conglomerate inclusions and axonal "spheroids" in spinal cord motoneurons (Corbo and Hays, 1992;Munoz et al, 1988;Sobue et al, 1990), and pyramidal cells of the motor cortex (Troost et al, 1992). Moreover, cystatin C-containing Bunina bodies are found in the cell bodies of motoneurons in ALS (Okamoto et al, 1993;Sasaki and Maruyama, 1994).…”