Amyotrophic Lateral Sclerosis(ALS):Will There Be A Cure?

ALS,also known as Lou Gehrig's Disease,is a devastating neurodegenerative disorder caused by selective loss of motor neurons. Over the past 25 years a major breakthrough in ALS research is the discovery that Mutations in the gene Cu/Zn superoxide dismutase type1（SOD1） are a cause of familial ALS（FALS）. The FALS-linked SOD1 variants are susceptible to posttranslational oxidative modifications,and subsequently become misfolded. Failure in degradation of the misfolded SOD1 by ubiquitin and/or autophagy proteasome systems results in accumulation of SOD1 aggregates and triggers a toxic cascade leading to motor neuron degeneration. Notably,wild type SOD1,when modified post-translationally,undergoes aberrant conformational changes and acquires toxic properties similar to FALS-associated SOD1 variants. Thus,misfolded SOD1 is a common toxic factor to both familial and sporadic ALS cases. Selective clearance of misfolded SOD1 is therefore a rational approach towards developing effective therapies for ALS. We have recently developed a peptide-direct protein knockdown system that rapidly and selectively degrades misfolded SOD1 through a chaperone-mediated autophagy pathway in vitro and in vivo. The peptide consists of a cell membrane-penetrating domain that allows the peptide to cross the blood brain barrier and plasma membrane following peripheral delivery,a cytosolic carboxyl terminal region of the Derlin1 CT4 motif that selectively binds to misfolded SOD1,and a chaperone-mediated autophagy targeting motif（CTM） that directs the peptide-protein complex for lysosomal degradation. Co-expression of the peptide with either the G93 A or the G37 R mutations of human SOD1 shows a significant reduction of the levels of both G93 A and G37 R,but not the wild type SOD1 in the control group. Inducing misfolding of human SOD1 by serum deprivation or increasing lysosomal activity robustly increases the knockdown efficiency of misfolded SOD1. The knocking-down of the peptide can be completely abolished when either the CT4 domain or the CTM domain is mutated. Our in vitro data so far shows that the peptide system effectively knocks down misfolded SOD1 in a dose,time and lysosomal activity-dependent manner. Intravenous injection of a single dose(10 mg·kg-1) of the 37-aa synthetic peptide in the G37 R and the G93 A mice resulted in a 57% reduction of misfolded SOD1 in 24 hours and 70% in 48 h in the brain and spinal cord. Levels of the misfolded SOD1 could recover in one week after a single administration. IP injection at 10 mg·kg-1（q.o.d） significantly delayed（or almost prevented in a few cases） the onset of the disease. We are cautiously optimistic that the peptide-direct protein knockdown system might be developed into a cure for ALS.