Reduced VGLUT2 expression increases motor neuron viability in Sod1(G93A) mice.
Glutamate-induced excitotoxicity has been suggested to influence pathogenesis in amyotrophic lateral sclerosis (ALS). Vesicular glutamate transporters (VGLUTs) are responsible for transport of glutamate into synaptic vesicles. Nerve terminals that envelop motor neurons in the spinal cord contain VGLUT2 and are likely responsible for most glutamate release on motor neurons. The role of VGLUT2 in ALS and its potential role to influence motor neuron survival have not previously been studied. Here, in a mouse model of ALS, we show that genetic reduction of VGLUT2 protein levels rescues motor neurons in the lumbar spinal cord and in the brainstem as well as neuromuscular junctions in tibialis anterior. Although the number of remaining motor neurons increased, neither disease onset nor life span was affected. We also show that the motor neuron subpopulation-specific markers calcitonin/calcitonin-related polypeptide alpha (Calca) and estrogen related receptor beta (ERRbeta) respond in a similar way to reduced VGLUT2 as the whole motor neuron population suggesting that the rescued motor neurons are not of a particular motor unit type. Taken together, this suggests that reduced levels of VGLUT2 decrease motor neuron degeneration but do not prevent loss of motor neuron function in the SOD1(G93A) mouse model for ALS.
Wootz
Hanna
H
Department of Neuroscience, Uppsala University, 75123 Uppsala, Sweden. hanna.wootz@neuro.uu.se
Enjin
Anders
A
Wallén-Mackenzie
Asa
A
Lindholm
Dan
D
Kullander
Klas
K
D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology; D000818:Animals; D001933:Brain Stem / Q000503:physiopathology; D002116:Calcitonin / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology*; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology; D009410:Nerve Degeneration / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000503:physiopathology; D011498:Protein Precursors / Q000378:metabolism; D013116:Spinal Cord / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism*
C000606589:CALCA protein, human; C000606590:Calca protein, mouse; D047629:Estrogen Receptor beta; D011498:Protein Precursors; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D002116:Calcitonin; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D015740:Calcitonin Gene-Related Peptide