Our research
The importance of local translation
Neurons are highly polarized cells, which can have very long axons—for some, motor neurons reach up to one meter in length. This poses a challenge for the homeostatic regulation of protein concentration at the synapses such as neuromuscular junctions, whose loss is one of the earliest events in ALS. To overcome these distance constraints neurons selectively transport and localize mRNAs along the axons and to synapses with a set of RNA binding proteins to locally produce proteins. While a wealth of data has led to consensus that protein synthesis occurs in mature dendrites and growth cones, there has been much less agreement about local translation in mature axons in mammalian cells.
Local axonal translation
We study the fundamental mechanisms governing local axonal translation in mature axons and neuromuscular junctions using mouse and human neurons cultured in microfluidic chambers, as well as several mouse models, employing multi -omics approaches such as spatial transcriptomics and proteomics and compartment-specific sequencing.
Protein aggregation
We also explore how liquid-liquid phase separation (LLPS)/aggregation and spreading of RNA-binding proteins contribute to disease using in vitro, cellular as well as mouse models.
Neuromuscular junction
We use in vitro co-culture models for functional neuromuscular junctions to identify therapeutics that can rescue or slow down the denervation process and/or improve innervation/reinnervation.
2019
Phenotypic Suppression of ALS/FTD-Associated Neurodegeneration Highlights Mechanisms of Dysfunction
Bartoletti M, Bosco DA, Da Cruz S, Lagier-Tourenne C, Liachko N, Markmiller S, Webster KM, Wharton KA. Journal of Neuroscience. 2019 Oct 16;39(42):8217-8224
doi: 10.1523/JNEUROSCI.1159-19.2019
Membralin deficiency dysregulates astrocytic glutamate homeostasis leading to ALS-like impairment
Jiang LL, Zhu B, Zhao Y, Li X, Liu T, Pina-Crespo J, Zhou L, Xu W, Rodriguez MJ, Yu H, Cleveland DW, Ravits J, Da Cruz S, Long T, Zhang D, Huang TY, Xu H. Journal of Clinical Investigation. 2019 May 21;129(8):3103-3120
doi: 10.1172/JCI127695
An endogenous peptide marker differentiates SOD1 stability and facilitates pharmacodynamic monitoring in SOD1 amyotrophic lateral sclerosis
Gertsman I, Wuu J, McAlonis-Downes M, Ghassemian M, Ling K, Rigo F, Bennett F, Benatar M, Miller TM, Da Cruz S. Journal of Clinical Investigation Insight. 2019 May 16;4(10):e122768
doi:10.1172/jci.insight.122768
Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death
Gasset-Rosa F, Lu S, Yu H, Chen C, Melamed Z, Guo L, Shorter J, Da Cruz S*, Cleveland DW*. Neuron. 2019 Apr 17;102(2):339-357.e7
doi: 10.1016/j.neuron.2019.02.038.
- Covered on Alzforum
- Cover of Neuron
Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis
Ling SC, Dastidar SG, Tokunaga S, Ho WY, Lim K, Ilieva H, Parone PA, Tyan SH, Tse TM, Chang JC, Platoshyn O, Bui NB, Bui A, Vetto A, Sun S, McAlonis-Downes M, Han JS, Swing D, Kapeli K, Yeo GW, Tessarollo L, Marsala M, Shaw CE, Tucker-Kellogg G, La Spada AR, Lagier-Tourenne C, Da Cruz S, Cleveland DW. Elife. 2019 Feb 12;8:e40811
doi: 10.7554/eLife.40811
Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration
Melamed Z, López-Erauskin J, Baughn MW, Zhang O, Drenner K, Sun Y, Freyermuth F, McMahon MA, Beccari MS, Artates JW, Ohkubo T, Rodriguez M, Lin N, Wu D, Bennett CF, Rigo F, Da Cruz S, Ravits J, Lagier-Tourenne C, Cleveland DW. Nature Neuroscience. 2019 Feb;22(2):180-190.
doi: 10.1038/s41593-018-0293-z.
- Covered on Alzforum