Mutations in the RNA-associated protein TDP-43 cause ALS and frontotemporal dementia (FTD), but how these aberrant forms cause neurodegeneration remains unclear (see Feb 2016 news, Jul 2016 news). A report in the August 17 Molecular Biology of the Cell online implicates impaired Bone Morphogenic Protein (BMP) signaling, which controls synaptic growth and function. Activated BMP receptors are typically internalized into early endosomes, where they regulate cytoskeletal architecture and downstream targets to modify transcription. The researchers, led by Avital Rodal of Brandeis University in Waltham, MA, demonstrate that in Drosophila models of both gain- and loss-of-function of TDP-43, BMP receptor distribution was shifted to recycling endosomes, which limit receptor signaling. Rerouting BMP receptors out of recycling endosomes by inhibiting Rab11 partially restored synaptic growth and larval motor function in the TDP-43 mutant larvae.
Deshpande M, Feiger Z, Shilton AK, Luo CC, Silverman E, Rodal AA. Role of BMP receptor traffic in synaptic growth defects in an ALS model. Mol Biol Cell. 2016 Aug 17. Epub ahead of print. [Pubmed].