VEGF alleviates ALS-CSF induced cytoplasmic accumulations of TDP-43 and FUS/TLS in NSC-34 cells.
Cytoplasmic mislocalisation and aggregation of TDP-43 and FUS/TLS proteins in spinal motor neurons contribute to the pathogenesis of the highly fatal disorder amyotrophic lateral sclerosis (ALS). We investigated the neuroprotective effect of VEGF on expression of these proteins in the motor neuronal cell line NSC-34 modelled to reminisce sporadic form of ALS. We studied the expression of TDP-43 and FUS/TLS proteins after exposure to ALS-CSF and following VEGF supplementation by quantitative confocal microscopy and electron microscopy. ALS-CSF caused cytoplasmic overexpression of both the proteins and stress-granule formation in the cells. These alterations were alleviated by VEGF supplementation. The related ultrastructural changes like nuclear membrane dysmorphism and p-bodies associated changes were also reversed. However the protein expression did not completely translocate to the nucleus, as some cells continued to show to cytoplasmic mislocalisation. Thus, the present findings indicate that VEGF alleviates TDP43 and FUS pathology by complimenting its role in controlling apoptosis and reversing choline acetyl transferase expression. Hence, VEGF appears to target multiple pathogenic processes in the neurodegenerative cascade of ALS.
Department of Neurology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029, India.
Shubham
S
Shantanu
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029, India.
K
K
Vijayalakshmi
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029, India.
S
S
Shruthi
Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029, India.
B K Chandrasekhar
BKC
Sagar
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029, India.
T N
TN
Sathyaprabha
Department of Neurology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029, India.
A
A
Nalini
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029, India.
Trichur R
TR
Raju
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029, India. Electronic address: alladiphalguni@gmail.com.
Phalguni Anand
PA
Alladi
D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid* / Q000473:pathology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002460:Cell Line; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D034702:RNA-Binding Protein FUS / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D015415:Biomarkers; D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
Confocal microscopy; Cytoplasmic mislocalisation; Electron microscopy; Immunocytochemistry; Nuclear membrane; P-bodies; Ribonuclear proteins; Stress granules; Vascular endothelial growth factor