ReviewNeurodegenerative Disease

RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration

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Science Translational Medicine  08 Nov 2017:
Vol. 9, Issue 415, eaah5436
DOI: 10.1126/scitranslmed.aah5436


  • Fig. 1. Characteristic neuropathology in ALS.

    (A and B) Hematoxylin-eosin– and Luxol fast blue (myelin stain)–stained sections of the medulla oblongata (A) and eighth thoracic spinal cord section (B) of patients with ALS are shown. (A) Loss of upper motor neurons in the hypoglossal nuclei (dashed circle) indicate degeneration of lower motor neurons in the spinal cord. Scale bar, 500 μm. (B) Lateral corticospinal tract degeneration indicating loss of upper motor neurons is characterized by myelinated axon loss (visualized as paler staining and by dashed lines). Scale bar, 5 mm. (C) Skein-like TDP-43–positive inclusions reveal intracytoplasmic thread-like structures within neurons in the medulla oblongata of the ALS patient from (A). (D) Cystatin C–containing inclusions in the motor neurons of an ALS patient are shown. Accumulated proteinaceous materials in this type of inclusion body are not known.

    Credit: M. Hatano; A. Kitterman/Science Translational Medicine
  • Fig. 2. ALS/FTD-associated proteins and a common pathogenic cascade.

    Many ALS/FTD-associated proteins participate in the intracellular RNA and protein quality control machineries. Mutant TDP-43, an RNA binding protein first identified in patients with ALS/FTD, disrupts the RNA quality control system, possibly leading to RNA dysregulation. ALS/FTD-associated mutant proteins in the protein quality control system cause dysregulation of the proteasome and autophagy pathways, resulting in formation of protein aggregates. These cascades may show cross-talk leading to neurodegeneration through two parallel pathways (A) or by convergence onto a single pathway (B). TBK1, TANK-binding kinase 1; SQSTM1, sequestosome-1; UBQLN2, ubiquilin2; CCNF, cyclin F; RAN, repeat-associated non-ATG.

    Credit: A. Kitterman/Science Translational Medicine
  • Fig. 3. Structure of ALS-associated RNA binding proteins.

    The glycine/serine-tyrosine-glycine/serine (G/S-Y-G/S) motif and the arginine/glycine/glycine repeat (RGG) motif, which are predicted to have prion-like properties, are shown. Thick black line shows the prion-like domain (PrLD) and the amino acid positions that it occupies. Mutations identified in ALS/FTD, distal myopathy, or both diseases are shown by red, blue, and green tick marks, respectively. Seven of the ALS-related RNA binding proteins contain a PrLD, but Matrin 3 does not. RRM, RNA recognition motif; GRD, glycine-rich domain.

    Credit: A. Kitterman/Science Translational Medicine
  • Fig. 4. A potential common pathogenic pathway for ALS/FTD.

    ALS/FTD-associated RNA binding proteins have a PrLD, RRM, and NLS. These mutant RNA binding proteins become mislocalized from the nucleus to the cytoplasm due to disruption in nucleocytoplasmic trafficking caused by, for example, C9orf72 repeat expansions, pathological aggregation of proteins, or mutations in the NLS (A). This loss of function mediated by nuclear depletion may be involved in RNA dysregulation that results in neurodegeneration (B). The mislocalized RNA binding proteins assemble as cytoplasmic RNA granules (membraneless organelles formed by liquid-liquid phase separation) mediated by PrLDs (C), and the local concentration of proteins increases. Mutations in PrLDs lead to the formation of toxic protein aggregates and accelerate the formation of pathological inclusions (D). Meanwhile, the protein quality control system contributes by removing aberrant RNA granules and pathological inclusions. However, mutations in regulators of autophagy and the proteasome, as well as proteins containing dipeptide repeats, can disrupt the protein quality control system (E), leading to increased accumulation of RNA granules and pathological inclusions. In a toxic gain of function, the aberrant RNA granules and pathological inclusions (with a core composition of RNA binding proteins) trap RNAs and cause RNA dysregulation (F), leading to neuronal degeneration in ALS/FTD. Pathological protein aggregates may be transmitted from neuron to neuron in a “prion-like” manner (G). Complex interactions among these processes lead to the development of ALS/FTD.

    Credit: A. Kitterman/Science Translational Medicine

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