IntroductionAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that widely affects motor neurons of the CNS. About 20% of patients with ALS have familial ALS (fALS). One of the classic models of ALS are SOD1G93A mice. Misfolded SOD1 protein can be overexpressed in motor neurons, which results in progressive paralysis of the limbs of mice. There is still no effective treatment for ALS. In recent years, the treatment of ALS by regulating autophagy has become a research hotspot. Autophagy obstacles have been confirmed to be one of the early pathological events of ALS. Rab7 is a member of the Ras superfamily and plays a key role in the late stage of autophagy. In our previous studies, we found that prenoylation of Rab7 was inhibited in the ALS model. Prenylation is a post-translational modification in which farnesyl or geranylgeranyl groups are covalently linked to target proteins. Based on these findings, we proposed the novel idea that the regulation of RabGGTB (the β-subunit of RabGGTase) mediated prenylation modification of Rab7, and that this can be used as a prevention and treatment of ALS associated with abnormal protein accumulation.MethodsIn the present study, RabGGTB was overexpressed in mouse spinal cord motoneurons by using adeno-associated virus as vector. Then immunofluorescence quantitative analysis was used for pathological study. The body weight, footprint analysis, the accelerating rotarod test, and neurological deficits score were used to evaluate animal behavior.ResultsOur results show that the protein level of RabGGTB was significantly increased in the lumbar and thoracic regions of spinal cord motoneurons of injected mice. Furthermore, the onset time and survival time of SOD1G93A mice injected with AAV9-RabGGTB-GFP+ were delayed compared with those of mice without overexpression. At the same time, we also observed a decrease in SOD1 misfolded and glial overactivation in the lumbar spinal cord of these SOD1G93A mice.ConclusionThe findings reported here show that RabGGTB plays a significant role in the pathogenesis of SOD1G93A mice and with great therapeutic potential for reducing abnormal aggregation of SOD1 in ALS.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by the formation of intracellular protein aggregations and the selective loss of motor neurons. Inflammatory response imbalance was considered to be a risk factor and disease-modifier and involved in the regulation of abnormal protein aggregation in ALS disease. The “microbiota-gut-brain axis” is a bidirectional communication system, which has been shown play some regulatory role in neuroinflammation and abnormal protein aggregation of neurodegenerative disorders. But whether probiotics can exert effects on ALS disease through “microbiota-gut-brain axis” is not clear. In our present study, we first report on superoxide dismutase 1-positive aggregates in intestinal myenteric neurons of SOD1G93A mice. This phenomenon was accompanied by structural disorder of myenteric neurons and enteric glial cells, impaired barrier function and overactivated pro-inflammatory response in intestine. This pathological change is different in colon and ileum, suggesting that it may be related to the difference of microbiota in their lumen. Oral administration of a multi-strain probiotic mixture containing Lactobacillus acidophilus, Bifidobacterium longum and Enterococcus faecalis not only improved the gut barrier function and pro-inflammatory response of spinal cord and intestine but also reduced aberrant SOD1 aggregation in myenteric neurons and spinal cord. This effect is accompanied by the alteration of gut microbiota composition and the increased level of short-chain fatty acids. Together, these findings might imply a potential benefit of microbiota-gut-brain axis axis-based therapy in ALS.