Characterization of mitochondria-associated ER membranes in the enteric nervous system under physiological and pathological conditions.

Alterations in endoplasmic reticulum (ER)-mitochondria associations and in mitochondria-associated ER membrane (MAM) behavior have been reported in the brain in several neurodegenerative diseases. Despite the emerging role of the gut-brain axis in neurodegenerative disorders, the biology of MAM in the enteric nervous system (ENS) has not previously been studied. Therefore, we set out to characterize the MAM in the distal colon of wild-type C57BL/6J mice and senescence-accelerated mouse prone 8 (SAMP8), a mouse model of age-related neurodegeneration. We showed for the first time that MAMs are widely present in enteric neurons and that their association is altered in SAMP8 mice. We then examined the functions of MAMs in a primary culture model of enteric neurons and showed that calcium homeostasis was altered in SAMP8 mice when compared with control animals. These findings provide the first detailed characterization of MAMs in the ENS under physiological conditions and during age-associated neurodegeneration. Further investigation of MAM modifications in the ENS in disease may provide valuable information about the possible role of enteric MAMs in neurodegenerative diseases.NEW & NOTEWORTHY Our work shows for the first time the presence of contacts between endoplasmic reticulum and mitochondria in the enteric neurons and that the dynamic of these contacts is affected in these cells from an age-related neurodegeneration mouse model. It provides new insights into the potential role of enteric mitochondria-associated endoplasmic reticulum membrane in neurodegenerative disorders.

High-resolution transcription maps reveal the widespread impact of roadblock termination in yeast.

Transcription termination delimits transcription units but also plays important roles in limiting pervasive transcription. We have previously shown that transcription termination occurs when elongating RNA polymerase II (RNAPII) collides with the DNA-bound general transcription factor Reb1. We demonstrate here that many different DNA-binding proteins can induce termination by a similar roadblock (RB) mechanism. We generated high-resolution transcription maps by the direct detection of RNAPII upon nuclear depletion of two essential RB factors or when the canonical termination pathways for coding and non-coding RNAs are defective. We show that RB termination occurs genomewide and functions independently of (and redundantly with) the main transcription termination pathways. We provide evidence that transcriptional readthrough at canonical terminators is a significant source of pervasive transcription, which is controlled to a large extent by RB termination. Finally, we demonstrate the occurrence of RB termination around centromeres and tRNA genes, which we suggest shields these regions from RNAPII to preserve their functional integrity.