Smcr8, short for Smith-Magenis syndrome chromosome region, candidate 8, is a protein-coding gene. It forms a complex with C9orf72, and this complex is involved in multiple biological processes such as membrane trafficking, autophagy, and regulation of primary ciliogenesis [1,2,3,4,5]. Autophagy is a process of intracellular material degradation, and the C9orf72-Smcr8 complex also seems to play a role in lysosomal degradation and exocytosis, with implications for MTORC1 signaling [3].

In Smcr8 knockout (KO) mice, there are motor behavior deficits similar to those in C9ALS/FTD mouse models, along with axonal swellings in the spinal cord and neuromuscular junctions. These deficits are due to impaired autophagy-lysosomal functions caused by disrupted axonal transport in mutant motor neurons. Smcr8 deficiency also exacerbates autophagy-lysosomal impairment in C9orf72 KO mice, and Smcr8 haploinsufficiency exacerbates axonal degeneration and toxicity in a C9ALS/FTD mouse model [7]. Additionally, Smcr8 KO in mice leads to splenomegaly with autoimmune phenotypes, and its loss causes a decrease in C9orf72 protein levels and upregulation of MTORC1 and AKT, affecting the macroautophagy-lysosome pathways and spine density in neurons [6].

In conclusion, Smcr8 is crucial in regulating autophagy-lysosomal functions, MTORC1 and AKT signaling, and tissue homeostasis. Studies using Smcr8 KO mouse models have provided significant insights into its role in diseases like ALS and FTD, highlighting its potential as a therapeutic target for these neurodegenerative disorders.