A Shotgun Proteomics Approach Reveals a New Toxic Role for Alzheimer's Disease Aβ Peptide: Spliceosome Impairment.
Proteomic changes have been described in many neurodegenerative diseases, including Alzheimer's disease (AD). However, the early events in the onset of the pathology are yet to be fully elucidated. A cell model system in which LAN5 neuroblastoma cells were incubated for a short time with a recombinant form of Aβ42was utilized. Proteins extracted from these cells were subjected to shotgun proteomics analysis by LTQ-Orbitrap-MS followed by label-free quantitation. By bioinformatics tools we found that the most significant of those found to be up-regulated were related to cytoskeletal dynamics (Rho related) and membrane-related processes. The most significant of the down-regulated proteins were hnRNP-related. In particular, hnRNPs involved in ribosomal biogenesis and in splicing were down-regulated. The latter of these processes stood out as it was highlighted ubiquitously and with the highest significance in the results of every analysis. Furthermore, our findings revealed down-regulation at every stage of the splicing process through down-regulation of every subunit of the spliceosome. Dysregulation of the spliceosome was also confirmed using a Western blot. In conclusion, these data suggest dysregulation of the proteins and processes identified as early events in pathogenesis of AD following Aβ accumulation.
Istituto di Biomedicina ed Immunologia Molecolare "A. Monroy" (IBIM) , Via Ugo La Malfa 153, 90146 Palermo, Italy.
Domenico
0000-0002-4325-417X
D
Nuzzo
Istituto di Biofisica (IBF) , Via Ugo La Malfa 153, 90146 Palermo, Italy.|Euro-Mediterranean Institute of Science and Technology , 90146 Palermo, Italy.
Luigi
L
Inguglia
Istituto di Biomedicina ed Immunologia Molecolare "A. Monroy" (IBIM) , Via Ugo La Malfa 153, 90146 Palermo, Italy.
Jessica
J
Walters
Istituto di Biomedicina ed Immunologia Molecolare "A. Monroy" (IBIM) , Via Ugo La Malfa 153, 90146 Palermo, Italy.
Pasquale
P
Picone
Istituto di Biomedicina ed Immunologia Molecolare "A. Monroy" (IBIM) , Via Ugo La Malfa 153, 90146 Palermo, Italy.
Marta
0000-0002-7934-1275
M
Di Carlo
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology; D020543:Proteome / Q000187:drug effects / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology*; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D020543:Proteome; D011994:Recombinant Proteins
Alzheimer’s disease; early events in AD; shotgun proteomics; spliceosome