Increased axonal ribosome numbers is an early event in the pathogenesis of amyotrophic lateral sclerosis.
Myelinating glia cells support axon survival and functions through mechanisms independent of myelination, and their dysfunction leads to axonal degeneration in several diseases. In amyotrophic lateral sclerosis (ALS), spinal motor neurons undergo retrograde degeneration, and slowing of axonal transport is an early event that in ALS mutant mice occurs well before motor neuron degeneration. Interestingly, in familial forms of ALS, Schwann cells have been proposed to slow disease progression. We demonstrated previously that Schwann cells transfer polyribosomes to diseased and regenerating axons, a possible rescue mechanism for disease-induced reductions in axonal proteins. Here, we investigated whether elevated levels of axonal ribosomes are also found in ALS, by analysis of a superoxide dismutase 1 (SOD1)(G93A) mouse model for human familial ALS and a patient suffering from sporadic ALS. In both cases, we found that the disorder was associated with an increase in the population of axonal ribosomes in myelinated axons. Importantly, in SOD1(G93A) mice, the appearance of axonal ribosomes preceded the manifestation of behavioral symptoms, indicating that upregulation of axonal ribosomes occurs early in the pathogenesis of ALS. In line with our previous studies, electron microscopy analysis showed that Schwann cells might serve as a source of axonal ribosomes in the disease-compromised axons. The early appearance of axonal ribosomes indicates an involvement of Schwann cells early in ALS neuropathology, and may serve as an early marker for disease-affected axons, not only in ALS, but also for other central and peripheral neurodegenerative disorders.
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
Mark H G
MH
Verheijen
Laboratory of Molecular Neurobiology, Department of Neuroscience, "Mario Negri" Institute for Pharmacological Research, Milan, Italy.
Marco
M
Peviani
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
Rita
R
Hendricusdottir
Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
Erin M
EM
Bell
Department of Pathology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Martin
M
Lammens
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
August B
AB
Smit
Laboratory of Molecular Neurobiology, Department of Neuroscience, "Mario Negri" Institute for Pharmacological Research, Milan, Italy.
Caterina
C
Bendotti
Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
Jan
J
van Minnen
D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D001369:Axons / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009410:Nerve Degeneration / Q000473:pathology; D012270:Ribosomes / Q000473:pathology*; D012583:Schwann Cells / Q000473:pathology