Title: Molecular dynamics of corticospinal development as a contributor to selective vulnerability in ALS
Abstract: ALS and FTD centrally involve degeneration of function-specific subtypes of cortical subcerebral projection neurons (SCPN): in ALS, corticospinal neurons (CSN) controlling voluntary movement; in FTD, closely related von Economo neurons (VENs) and fork cells regulating emotion and cognition. Why these closely related neuronal subtypes are especially vulnerable in both ALS/FTD is unknown and likely key to prevention/therapy, since in both patients and mouse models carrying familial ALS/FTD mutations (e.g. SOD1, TDP-43, FUS, C9orf72), most neurons in brain and most body cells express the variant gene, but only specific neuronal subtypes degenerate. Molecular differences between affected subtypes and other even closely related neurons might render affected neurons more vulnerable to dysfunction from mis-expression/mutation. To identify potential molecular differences between subtypes, we performed a “multi-omic” investigation of RNA expression, translation efficiency, and protein abundance across multiple CSN subpopulations at multiple early, post-natal stages, and compared with similar data sets from unaffected callosal projection neurons (CPN) and corticothalamic projection neurons (CThPN). We observe at “baseline”, expression differences in multiple known ALS/FTD risk genes between CSN and unaffected subtypes early in their postnatal development in wild-type mice, which might explain why mutation of these genes or other perturbations frequently lead to selective loss of CSN in ALS.
Additionally, we investigate whether subtype-specific subcellular localization of specific RNAs and proteins render corticospinal neurons (CSN) selectively vulnerable to degeneration in ALS by comparison of CSN presynaptic vs. soma molecular machinery in pre-onset hSOD1G93A vs. WT mice. Dysfunctional localization of molecules to CSN synapses might contribute to selective vulnerability of corticospinal circuitry in ALS. We have purified and quantitatively analyzed CSN synaptosomes, using optimized approaches for labeling and sorting subcellular material from specific subtypes, from CSN in WT and hSOD1G93A mice, and compare RNA abundances to identify mRNAs with altered axonal/synaptic localization as novel factors potentially contributing to vulnerability of corticospinal circuitry.