doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Amyotrophic lateral sclerosis (ALS) is a progressively fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. We used 380 post-mortem tissue RNA-seq transcriptomes from 154 ALS cases and 49 control individuals from cervical, thoracic, and lumbar spinal cord segments to investigate the gene expression response to ALS. We observed an increase in microglia and astrocyte expression, accompanied by a decrease in oligodendrocytes. By creating a gene co-expression network in the ALS samples, we identify several activated microglia modules that negatively correlate with retrospective disease duration. We map molecular quantitative trait loci and find several potential ALS risk loci that may act through gene expression or splicing in the spinal cord and assign putative cell-types for FNBP1, ACSL5, SH3RF1 and NFASC. Finally, we outline how repeat expansions that alter splicing of C9orf72 are tagged by common variants, and use this to suggest ATXN3 as a putative risk gene.

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Microbial cells must continually adapt their physiology in the face of changing environmental conditions. Archaea living in extreme conditions, such as saturated salinity, represent important examples of such resilience. The model salt-loving organism Haloferax volcanii exhibits remarkable plasticity in its morphology, biofilm formation, and motility in response to variations in nutrients and cell density. However, the mechanisms regulating these lifestyle transitions remain unclear. In prior research, we showed that the transcriptional regulator, TrmB, maintains the rod shape in the related species Halobacterium salinarum by activating the expression of enzyme-coding genes in the gluconeogenesis metabolic pathway. In Hbt. salinarum, TrmB-dependent production of glucose moieties is required for cell surface glycoprotein biogenesis. Here we use a combination of genetics, quantitative phenotyping, and gene expression assays to demonstrate that TrmB is essential for growth under gluconeogenic conditions in Hfx. volcanii. The ∆ trmB strain rapidly accumulated suppressor mutations in a gene encoding a novel transcriptional regulator, which we name Trm Bsu ppressor, or TbsP. TbsP is required for adhesion to abiotic surfaces (i.e. biofilm formation), and maintains wild type cell morphology, and motility. TrmB and TbsP jointly regulate the glucose-dependent transcription of gapII, which encodes an important gluconeogenic enzyme. We conclude that TrmB and TbsP co-regulate gluconeogenesis, with downstream impacts on lifestyle transitions in response to nutrients in Hfx. volcanii.

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