Pavel Abaffy (Czech Republic)
Czech Academy of Sciences Institute of BiotechnologyAuthor Of 1 Presentation
ATTENUATION OF REACTIVE GLIOSIS SLOWS DOWN PROGRESSION OF ALS
Abstract
Aims
ALS is a neurodegenerative disease affecting motor neurons. Riluzole, the only established treatment, increases the survival by only months. Reactive gliosis is a prominent and early neuropathological hallmark of ALS and astrocytes emerge as key players in ALS pathogenesis. We previously demonstrated that attenuation of reactive gliosis facilitated progression of two other neurodegenerative diseases, Batten disease and Alzheimer’s disease. We aim at dissecting the role of reactive astrocytes in ALS and identifying potential therapeutic interventions.
Methods
Mice carrying a Vps54 mutation, which develop ALS-like symptomatology, were crossed with mice with attenuated reactive gliosis (GFAP–/–Vim–/–).
Results
ALS mice on the GFAP–/–Vim–/– background survived longer than ALS mice, the disease progressed more slowly, with higher number of motor neurons and larger proportion of homeostatic and neuroprotective astrocytes in the cervical spinal cord. Genes related to oxidative phosphorylation and mitochondria were up-regulated in ALS vs. WT primary astrocytes, but down-regulated in ALS GFAP–/–Vim–/– vs. ALS astrocytes. Quantitative proteomics showed upregulation of proteins involved in synapses/neural plasticity in the spinal cord of ALS GFAP–/–Vim–/– vs. ALS mice; the scenario of increased neural plasticity was further supported by increased synaptophysin and GAP43 levels in cervical spinal cord of ALS GFAP–/–Vim–/– vs. ALS mice. Withaferin A administration decreased the brain levels of GFAP, and 5 week long treatment of ALS mice with withaferin A reduced paw atrophy and gait impairment, and improved grip strength, and was comparable with the effects of genetic attenuation of reactive gliosis.
Conclusions
These data suggest that astrocyte reactivity in ALS is maladaptive, resulting in neurotoxicity and inhibition of regenerative responses. Thus, astrocyte reactivity presents an important target in ALS.