Metabolic aspects behind ageing and neurodegeneration reveal new ways forward for therapy in motorneurone(ALS) and Parkinson diseases

Human beings evolved to run over a relatively short evolutionary time scale, ~1 million years, 2-3 million years ago, markedly increasing metabolic rate and VO2max, compared with other primates, while increasing brain size,and lifespan. Ageing leads to precise declines in performance and metabolism(VO2max): are there links with ageing-related diseases? Glucocerebrosidase(GCase;GBA1 subtype) mutations are the most common cause of Parkinson Disease,where there is lysosomal disruption and a reciprocal feedback between glucosylceramide and a-synuclein. We have shown that GBA2 is elevated and, using metabolomics, that ceramide and glucosylceramide levels are critically modified presymptomatically and at early stage in the spinal cord of superoxide dismutase1 mutant mice(SOD1G86R, ALS model),and lipid metabolism is massively changed at end stage disease. Modification of glucosylceramide synthase(GCS), and GCase activites shows that inhibiting GCS is deleterious and inhibiting GCase is beneficial to both neuromuscular junction function in sciatic nerve crush, and also grip strength and survival in the SOD1G86R model. Ambroxol(3 mmol·L-1 in drinking water), a glucocerebrosidase chaperone, accelerated recovery of NMJ function in sciatic nerve crush, and ameliorated grip strength and survival in the SOD1G86R model. Ambroxol is phase 2 ready in ALS and starting phase 3 in Parkinson disease.

Sciatic nerve injury alters the spatial arrangement of neurons and glial cells in the anterior horn of the spinal cord

The spatial arrangement of the cell is important and considered as underlying mechanism for mathematical modeling of cell to cell interaction.The ability of cells to take on the characteristics of other cells in an organism,it is important to understand the dynamical behavior of the cells.This method implements experimental parameters of the cell-cell interaction into the mathematical simulation of cell arrangement.The purpose of this research was to explore the three-dimensional spatial distribution of anterior horn cells in the rat spinal cord to examine differences after sciatic nerve injury.Sixteen Sprague-Dawley male rats were assigned to control and axotomy groups.Twelve weeks after surgery,the anterior horn was removed for first-and second-order stereological studies.Second-order stereological techniques were applied to estimate the pair correlation and cross-correlation functions using a dipole probe superimposed onto the spinal cord sections.The findings revealed 7% and 36% reductions in the mean volume and total number of motoneurons,respectively,and a25% increase in the neuroglial cell number in the axotomized rats compared to the control rats.In contrast,the anterior horn volume remained unchanged.The results also indicated a broader gap in the pair correlation curve for the motoneurons and neuroglial cells in the axotomized rats compared to the control rats.This finding shows a negative correlation for the distribution of motoneurons and neuroglial cells in the axotomized rats.The cross-correlation curve shows a negative correlation between the motoneurons and neuroglial cells in the axotomized rats.These findings suggest that cellular structural and functional changes after sciatic nerve injury lead to the alterations in the spatial arrangement of motoneurons and neuroglial cells,finally affecting the normal function of the central nervous system.The experimental protocol was reviewed and approved by the Animal Ethics Committee of Shahid Beheshti University of Medical Sciences(approval No.IR.SBMU.MSP.REC1395.375) on October 17,2016.