Table 4.
MALDI-MS proteomics studies for mechanistic insight into ALS and FTD.
| Sample | Summary | Remarks | References |
|---|---|---|---|
| Human samples | |||
| ALS spinal cord | CA-I is biotinylated alongside SOD1 + immunoreactive to a SOD1 antibody | Suggests altered CO2 transport and cellular pH homeostasis | Liu et al., 2010 |
| sALS spinal cord | 18 proteins ↑/↓, GFAP = most abundant | Proteins involved in apoptosis and cytoskeleton stabilization | Ekegren et al., 2006 |
| FTLD frontal cortex | 24 proteins ↑/↓ = UCHL1 and oxidative stress proteins | Ubiquitin-mediated degradation and oxidative stress response altered | Schweitzer et al., 2006 |
| FTLD-tau (Pick disease) brain | ↑ GFAP with glycoxidation and lipoxidation | GFAP = target of oxidative damage | Muntane et al., 2006 |
| FTD temporal lobe | N-terminal fragment ProSAAS enriched in tauopathies | ProSAAS is an inhibitor of neuroendocrine peptide processing - enrichment may cause functional perturbation | Kikuchi et al., 2003 |
| FTD CSF | ↑/↓ ProSAAS, PEDF, RBP, apoE, HP, and ALB | Comparative proteomics to establish pathophysiological mechanisms | Davidsson et al., 2002 |
| sALS spinal cord | ↑ Detergent-insoluble proteins (ACO2, HSC70, and PPIase A) + intermediate filaments, chaperones and mitochondrial proteins, some tyrosine-nitration | Aggregation-prone proteins and nitrative stress contribution to inclusion pathology | Basso et al., 2009 |
| Animal models | |||
| SOD1G93A mouse synaptic fractions | STAU1+dynein interactions via PP1B | STAU1 regulates mRNA localization in axons and synapses. Disrupted = toxicity | Gershoni-Emek et al., 2016 |
| SOD1G93A mouse facial and trigeminal nuclei | ↑/↓ various proteins, ↑RPS19 | Proteins contributing to pathology via comparative brain region proteomics | Acquadro et al., 2014 |
| SOD1H46R/H48Q mouse spinal cord | Association between SOD1 surface hydrophobicity SOD1 and conformations | HSF1 activation may mitigate ALS pathology | Lin et al., 2013 |
| SOD1G93A and G127X mouse spinal cord | Mutant SOD1 interactors = chaperones, HSC70 abundant | Chaperone depletion is not involved in SOD1 mutations of ALS | Zetterstrom et al., 2011 |
| SOD1G85R and G93A mouse eMNs | ↑ CRMP4a = axonal degeneration and MN cell death ↓ CRMP4a protective | CRMP4a pathologically involved in ALS | Duplan et al., 2010 |
| SOD1G127X mouse spinal cord | 54 proteins ↑/↓ = oxidative stress, mitochondrial, cellular assembly/organization and protein degradation | Altered pathways may contribute to disease | Bergemalm et al., 2009 |
| SOD1G93A mice spinal cord | ↑/↓ proteins = mitochondrial dysfunction, aggregation and stress response | Potential presymptomatic targets | Massignan et al., 2007 |
| SOD1G93A mouse spinal cord | ↑ Carbonylation of SOD1, TCTP, UCHL1, and CRYAB | Oxidative modification contributing factor to ALS | Poon et al., 2005 |
| SOD1G93A mouse spinal cord | Peroxidation of DRP-2, HSP70, and ENO1 | Supports oxidative stress as a major pathological mechanism | Perluigi et al., 2005 |
| hTau40P301L mouse brain | ↓ Complex I activity, ↑ antioxidant enzymes, altered lipid peroxidation | Tau pathology involves mitochondrial and oxidative stress | David et al., 2005 |
| Cell models and in vitro studies | |||
| N2A cells expressing ATXN2, FUS, C9ORF72, OPTN, TDP-43, and UBLQN2 WT/mutants | Interactome of ATXN2, C9ORF72, FUS, OPTN, TDP-43, and UBQLN2 (hundreds of proteins) | Strong interactome overlap for ATXN2, FUS, and TDP-43 distinct from OPTN and UBQLN2 | Blokhuis et al., 2016 |
| C4F6 hybridoma cells expressing SOD1 mutants | D92/D96 important for SOD1-C4F6 antibody interaction | C4F6 antibody epitope in SOD1 is a potential therapeutic target | Rotunno et al., 2014 |
| COS7 cells expressing PGRN | 4 N-glycosylation sites of PGRN | PGRN glycosylation may contribute to disease | Songsrirote et al., 2010 |
| N2A cells treated with cadmium | Cadmium = ↑/↓ proteins = cellular structure, stress, chaperones, cell death/survival and ROS | Heavy metals suppress function of SOD1 | Huang et al., 2006 |
| NSC-34 cells expressing SOD1G93A | 170 proteins, ↑/↓ = mitochondrial, membrane transport, apoptosis, respiratory chain and chaperones | Mitochondrial protein changes = evidence for mitochondrial dysfunction | Fukada et al., 2004 |
| SOD1WT or N26D/N131D/N139D isolated from yeast | Deamidation mimic mutant SOD1 aggregated into amyloid fibrils faster than WT | Deamidation may be involved in SOD1 pathology | Shi et al., 2013b |
| In vitro (tau) | Acetylated tau prevents degradation of phosphorylated tau | Tau acetylation may be a therapeutic target | Min et al., 2010 |
↑, denotes increase; ↓, denotes decrease; ACO2, aconitase; ALB, albumin; apoE, apolipoprotein E; ATXN2, ataxin-2; C4F6; CA-I, carbonic anhydrase I; CRMP4a, collapsin response mediator protein 4a; CRYAB, alpha-crystallin B chain; CSF, cerebrospinal fluid; DRP-2, dystrophin-related protein 2; eMNs, embryonic motor neurons; ENO1, alpha-enolase; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; FUS, fused-in sarcoma; GFAP, glial fibrillary acidic protein; HP, haptoglobin; HSC70, heat shock cognate 71 kDA; HSP70, heat shock 70 kDa; OPTN, optineurin; PEDF, pigment epithelium-derived factor; PGRN, progranulin; PP1B, protein phosphatase 1-beta; PPIase A, peptidyl-prolyl cis-trans isomerase A; ProSAAS, proprotein convertase 1 inhibitor; RBP, retinol binding protein; ROS, reactive oxygen species; RPS19, 40S ribosomal protein S19; sALS, sporadic amyotrophic lateral sclerosis; STAU1, Staufen1; TCTP, translationally controlled tumor protein; TDP-43, TAR DNA-binding protein of 43 kDa; UBQLN2, ubiquilin-2; and UCHL1, ubiquitin carboxy-terminal hydrolase L1.