Author response: Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission

McCabe, Matthew P.; Cullen, Erin R; Barrows, Caitlynn M.; Shore, Amy N.; Tooke, Katherine I; Laprade, Kathryn A; Stafford, James M.; Weston, Matthew C.

doi:10.7554/elife.51440.sa2

Cited by 1 publication

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“…Although we did not pursue the entire interactome here, future studies investigating interactions between PUM1 and members of the mTOR pathway and anaphase-promoting complex should be very fruitful. As we were preparing this work, a new study demonstrated that mTORC1 is involved in postsynaptic responses in hippocampal glutamatergic neurons, whereas mTORC2 modulates presynaptic release (McCabe et al, 2020). Given the importance of proteostasis at the synapse-and its failure in many neurological diseases (Zoghbi & Bear, 2012)-the notion that different protein-regulating activities might be coordinated is intuitively appealing.…”

Section: Implications Of the Interactomementioning

confidence: 99%

Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

Botta

Chemiakine

et al. 2021

Preprint

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The RNA-binding protein (RBP) Pumilio1 (PUM1) is associated with two distinct diseases: a late-onset ataxia and a neurodevelopmental syndrome. The ataxia patients retain 75% of normal PUM1 levels, the syndromic patients ~50%, but this seems inadequate to explain the difference in phenotypes. We hypothesized that mild disease results from dysregulation of PUM1 targets, whereas severe disease involves disruption of PUM1 complexes and deregulation of shared targets. We therefore developed a PUM1 interactome for the murine brain and found that PUM1 shares targets with several RBP interactors (PUM2, FMRP, AGO2, and RBFOX3). PUM1 haploinsufficiency destabilizes these RBPs to varying degrees by brain region and sex, and alters expression of their shared targets, but the milder disease-causing mutation affects only PUM1-specific targets. These data indicate that dosage-sensitive proteins can produce different phenotypes by different mechanisms, and that there may be more intimate cooperation among RBPs than expected.

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Section: Implications Of the Interactomementioning

confidence: 99%