Stasimon/Tmem41b is required for cell proliferation and adult mouse survival.

Stasimon/Tmem41b is a transmembrane protein with phospholipid scrambling activity that resides in the endoplasmic reticulum and has been implicated in autophagy, lipid metabolism, and viral replication. Stasimon/Tmem41b has also been linked to the function of sensory-motor circuits and the pathogenesis of spinal muscular atrophy. However, the early embryonic lethality of constitutive knockout in mice has hindered the analysis of spatial and temporal requirements of Stasimon/Tmem41b in vivo. To address this, we developed a novel mouse line harboring a conditional knockout allele of the Stasimon/Tmem41b gene in which exon 4 has been flanked by loxP sites (Stas/Tmem41bCKO). Cre-mediated recombination of Stas/Tmem41bCKO generates a functionally null allele (Stas/Tmem41bΔ4) resulting in loss of protein expression and embryonic lethality in the homozygous mouse mutant. Here, using a ubiquitously expressed, tamoxifen inducible Cre recombinase in the homozygous Stas/Tmem41bCKO mice, we demonstrate that postnatal depletion of Stasimon/Tmem41b rapidly arrests weight gain in adult mice and causes motor dysfunction and death approximately three weeks after tamoxifen treatment. Moreover, we show that depletion of Stasimon/Tmem41b severely affects cell proliferation in mouse embryonic fibroblasts. This study provides new insights into the essential requirement of Stasimon/Tmem41b for cellular and organismal fitness and expands the experimental toolkit to investigate its functions in the mammalian system.

Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.

CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we show that the disordered N-terminal domain of CHCHD10 forms amyloid fibrils and report their cryoEM structure. Disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining the co-aggregation of the two proteins and linking CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration.

Clonal CD8 T Cells Accumulate in the Leptomeninges and Communicate with Microglia in Human Neurodegeneration.

Murine studies have highlighted a crucial role for immune cells in the meninges in surveilling the central nervous system (CNS) and influencing neuroinflammation. However, how meningeal immunity is altered in human neurodegeneration and its effects on CNS inflammation is understudied. We performed the first single-cell analysis of the transcriptomes and T cell receptor (TCR) repertoire of 104,635 immune cells from 55 postmortem human brain and leptomeningeal tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. RNA and TCR sequencing from paired leptomeninges and brain allowed us to perform lineage tracing to identify the spatial trajectory of clonal T cells in the CNS and its borders. We propose that T cells activated in the brain emigrate to and establish residency in the leptomeninges where they likely contribute to impairments in lymphatic drainage and remotely to CNS inflammation by producing IFNγ and other cytokines. We identified regulatory networks local to the meninges including NK cell-mediated CD8 T cell killing which likely help to control meningeal inflammation. Collectively, these findings provide not only a foundation for future studies into brain border immune surveillance but also highlight important intercellular dynamics that could be leveraged to modulate neuroinflammation.