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Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis.

The igfbp family proteins are key regulators of the biological activities of igfs, which play a pivotal role in controlling growth. Growth is highly variable between different fish species and even between growth stages and sexes within the same fish species. For determining the igfbps significantly associated to growth, we identified igfbp genes from the whole-wide genomes of mandarin fish Siniperca chuatsi and big-eye mandarin fish Siniperca kneri, and detected their expression profiles under different growth conditions. The results revealed that: 1) both mandarin fish and big-eye mandarin fish have 10 igfbp family members (igfbp-1a/b, igfbp-2a/b, igfbp-3, igfbp−4, igfbp-5a/b, and igfbp-6a/b), which are highly conserved among igfbp family members; 2) in early development, the expression of igf1 mRNA showed an increasing trend, igfbp-1a/b expression increased significantly with development and the expression trend was strongly similar to that of igf1; 3) variation of body sizes in adult revealed a strong correlation between the serum Gh content and igf1 mRNA expression level in the liver, and the expression levels of hepatic igfbp-2a/b, -4 showed a positive correlation; 4) serum Gh levels and the relative expression of hepatic igf1 mRNA were significantly higher in females than in males, the fold change in igfbp-1a in muscle, -2a, -5a in liver mRNA expression was strongly similar to that of igf1; 5) variation of the interspecific growth showed that the expression of serum Gh and hepatic igf1 mRNA in mandarin fish was significantly higher than that in big-eye mandarin fish. The expression of igfbps mRNA in mandarin fish was significantly higher than that in big-eye mandarin fish, except for igfbp-2a/2b in muscle and igfbp-6a in liver. Taken together, our results suggest that the different effects on growth of mandarin fish are regulated by the actions of different igfbps, where igfbp-1a/b, -2a/b, -4 and -5a may be a candidate for growth rate difference studies. The inherently low expression of Gh, igf1, and igfbps might have contributed to the slow growth of big-eye mandarin fish.

Marine shale reservoirs have experienced intense tectonic movements in southeastern Chongqing, resulting in widely developed folds, faults and bedding slip deformation. The gas content is of a wide range while the organic matter content and thickness are sufficient for shale gas accumulation. Here, we review previous work and present outcrop and core data from 11 shale wells around southeastern Chongqing to analyze and summarize tectonic types and their combinations, as well as their influence on shale gas preservation and enrichment. Fault and bedding slips are prevalent in shale reservoirs, and they apparently influence shale gas content. Bedding slip crush is usually formed at the bottom interval where the total organic content is high from intense horizontal compression. Bedding slip crushing and well-developed high-angle natural fractures form a net fracture system where shale gas is enriched in an anticline structure or lost to air in a syncline structure laterally. Strata dip is the key geological factor that controls bedding slip deformation in shale reservoirs in certain areas. According to the established bedding slip geological model, when bedding slip occurred, the critical strata dips of the lower Silurian Longmaxi Formation were 13.34°, respectively. Bedding slip crushed anticlines without faults and synclines without faults and bedding slip crushing are the two tectonic patterns that are favorable for shale gas preservation and enrichment, which should be the focus of further explorations of lower Paleozoic shale gas in southeastern Chongqing.