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. Author manuscript; available in PMC: 2019 Aug 15.
Published in final edited form as: Brain Res. 2018 Feb 17;1693(Pt A):75–91. doi: 10.1016/j.brainres.2018.02.018

Figure 2. mRNP assembly, axonal transport, and local translation defects in ALS/FTD.

Figure 2

An important hallmark of ALS/FTD pathology is the loss of TDP-43 or FUS mRBPs from the nucleus, and their accumulation in cytoplasmic aggregates. This defect is associated with, and perhaps triggered by reduced nuclear protein import through nuclear pore complexes (NPCs), which in turn further contribute to nucleocytoplasmic transport defects. The most common form of fALS is caused by GGGGCC hexanucleotide repeat expansions in the first intron of the C9orf72 gene locus, leading to the accumulation of nuclear RNA foci and DPR aggregates formed by RAN translation. These TDP-43 or FUS aggregates, as well as nuclear RNA foci and DPR aggregates, can trap mRNAs and mRBPs, impairing the assembly and transport of mRNA transport granules in axons. Affected transcripts include those encoding Neurofilament-L and MAP1B. This deficiency causes reduced local translation at axon terminals, leading to instability of microtubules (MTs) and synaptic defects.