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1.
Sci Adv ; 10(8): eadj0347, 2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38394210

ABSTRACT

Hexanucleotide repeat expansion in C9ORF72 (C9) is the most prevalent mutation among amyotrophic lateral sclerosis (ALS) patients. The patients carry over ~30 to hundreds or thousands of repeats translated to dipeptide repeats (DPRs) where poly-glycine-arginine (GR) and poly-proline-arginine (PR) are most toxic. The structure-function relationship is still unknown. Here, we examined the minimal neurotoxic repeat number of poly-GR and found that extension of the repeat number led to a loose helical structure disrupting plasma and nuclear membrane. Poly-GR/PR bound to nucleotides and interfered with transcription. We screened and identified a sulfated disaccharide that bound to poly-GR/PR and rescued poly-GR/PR-induced toxicity in neuroblastoma and C9-ALS-iPSC-derived motor neurons. The compound rescued the shortened life span and defective locomotion in poly-GR/PR expressing Drosophila model and improved motor behavior in poly-GR-injected mouse model. Overall, our results reveal structural and toxicity mechanisms for poly-GR/PR and facilitate therapeutic development for C9-ALS.


Subject(s)
Amyotrophic Lateral Sclerosis , Animals , Mice , Humans , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Dipeptides/pharmacology , Arginine/genetics , Sulfates , Drosophila/genetics , DNA Damage , DNA Repeat Expansion , C9orf72 Protein/genetics , C9orf72 Protein/metabolism
2.
Mol Neurobiol ; 49(2): 1055-68, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24217950

ABSTRACT

Alzheimer's disease is the most common dementia afflicting the elderly in modern society. This disease arises from the neurotoxicity elicited by abnormal aggregates of amyloid-ß (Aß) protein. Such aggregates form through the cleavage of amyloid precursor protein (APP) by ß-secretase and the subsequent proteolysis of the APP C-terminal fragment (APP-ßCTF or C99) by γ-secretase to yield Aß and APP intracellular domain (AICD). Recent evidence suggests that C99 and AICD may exert harmful effects on cells, suggesting that the proteolytic products of APP, including Aß, C99, and AICD, could play a pivotal role in neuronal viability. Here, we demonstrate that ligand-activated EphA4 signaling governs the proteostasis of C99, AICD, and Aß, without significantly affecting γ-secretase activity. EphA4 induced accumulation of C99 and AICD through a Lyn-dependent pathway; activation of this pathway triggered phosphorylation of EphA4, resulting in positive feedback of C99 and AICD proteostasis. Inhibition of EphA4 by dasatinib, a receptor tyrosine kinase inhibitor, effectively suppressed C99 and AICD accumulation. Furthermore, EphA4 signaling controlled C99 and AICD proteolysis through the ubiquitin-proteasome system. In conclusion, we have identified an EphA4-Lyn pathway that is essential for the metabolism of APP and its proteolytic derivatives, thereby providing novel pharmacological targets for the development of anti-Aß therapeutics for AD.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Proteolysis , Receptor, EphA4/metabolism , Signal Transduction/physiology , src-Family Kinases/physiology , Amyloid beta-Protein Precursor/genetics , Cells, Cultured , HEK293 Cells , Humans , Ligands , Receptor, EphA4/genetics , T-Lymphocytes/metabolism
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