The ataxia-telangiectasia disease protein ATM controls vesicular protein secretion via CHGA and microtubule dynamics via CRMP5
The autosomal recessive disease ataxia-telangiectasia (A-T) presents with cerebellar degeneration, immunodeficiency, radiosensitivity, capillary dilatations, and pulmonary infections. Most symptoms outside the nervous system can be explained by failures of the disease protein ATM as a Ser/Thr-kinase...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003589 |
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| Summary: | The autosomal recessive disease ataxia-telangiectasia (A-T) presents with cerebellar degeneration, immunodeficiency, radiosensitivity, capillary dilatations, and pulmonary infections. Most symptoms outside the nervous system can be explained by failures of the disease protein ATM as a Ser/Thr-kinase to coordinate DNA damage repair. However, ATM in adult neurons has cytoplasmic localization and vesicle association, where its roles remain unclear. Here, we defined novel ATM protein targets in human neuroblastoma cells, and filtered initial pathogenesis events in ATM-null mouse cerebellum. Profiles of global proteome and phosphoproteomics - both direct ATM/ATR substrates and overall phosphorylation changes - confirmed previous findings for NBN, MRE11, MDC1, CHEK1, EIF4EBP1, AP3B2, PPP2R5C, SYN1 and SLC2A1. Even stronger downregulation of ATM/ATR substrate phosphopeptides after ATM-depletion was documented for CHGA, EXPH5, NBEAL2 and CHMP6 as key factors of protein secretion and endosome dynamics, as well as for CRMP5, DISP2, PHACTR1, PLXNC1, INA and TPX2 as neurite extension factors. Prominent effects on semaphorin-CRMP5-microtubule signals and ATM association with CRMP5 were validated. As a functional consequence, microtubules were stabilized, and neurite retraction ensued. The impact of ATM on secretory granules confirms previous ATM-null cerebellar transcriptome findings. This study provides the first link of A-T neural atrophy to growth cone collapse and aberrant microtubule dynamics. |
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| ISSN: | 1095-953X |