Table 1.
Involvement of PERK pathway in neuropathology and oncology
| Neuro-degenerative diseases | Gene modification | Lines | Regulation | Techniques, brain area | Conclusive remarks | References |
|---|---|---|---|---|---|---|
| AD | – | Human postmortem brain tissue of AD | p-PERK ↑ | IHC; temporal cortex (mid), hippocampus | Neuroprotective at the initial stage but neurodegenerative in sustained activation | (48,49) |
| – | Tg2576, 5XFAD Tg |
p-eIF2α ↑ | WB, IHC; whole brain | Aβ overproduction | (52) | |
| PS1 mutant | C57BL/6 · 129/Sv | p-eIF2α ↑ CHOP ↑ |
WB; cortex, hippocampus | Increased cell death in familial AD | (54) | |
| APP | AppNL-G-F | p-eIF2α → CHOP → |
WB; cortex, hippocampus | ER stress not related to AD pathology | (57) | |
| Tg2576 | ||||||
| APP23 | ||||||
| APP/PS1 | APP(Swe)-Tg, PS(∆E9)-Tg | p-eIF2α ↑ CHOP ↑ |
||||
| APP/PS1/Mapt | 3XTg | |||||
| Transfection | APP-FLAG, C83-FLAG and AICD-FLAG | CHOP ↑ | WB, ELISA, MTT | Increased cell death | (60) | |
| Tau mutant | rTg4510 | p-PERK ↓ p-eIF2α ↓ |
WB, IHC; hippocampus | Prevented Tau mediated neurodegeneration | (67) | |
| APP/PS1 | P301S-Tau-Tg | p-eIF2α → CHOP → |
WB; hippocampus | No relation with AD pathogenesis | (56) | |
| APP/PS1 | C57BL/6 | p-PERK ↑ p-eIF2α ↑ |
WB: cerebral cortex | – | (51) | |
| PD | Dopaminergic neuron | Human autopsy brain | p-PERK ↑ p-eIF2α ↑ |
IHC; substantia nigra | No colocalization with α- synuclein | (69) |
| Co-transfection of A53T α-synuclein | PC12 cell | p-PERK ↑ | WB | Protected cell death | (68) | |
| Transfection | PC12 cell | ATF4 ↑ | WB; ventral midbrain | Promoted neuronal survival | (71,72) | |
| rAAV- mediated gene transfer | Sprague–Dawley rat | ATF4 ↑ | WB, IHC; substantia nigra | Neuron loss | (74) | |
| TH neuron | C57BL/6 | p-PERK ↑ p-eIF2α ↑ ATF4 ↑ |
WB; brain | Stress-mediated neuronal apoptosis | (76) | |
| HD | Transfection | PC6.3 cells | p-eIF2α ↑ | WB, ICC | Increased cell viability | (79) |
| Transfection | HEK293T | p-eIF2α ↑ | WB, ICC | Increased Htt expression | (81) | |
| Transfection | Striatal cells | p-eIF2α ↑ | WB, ICC | Decreased cell viability | ||
| Human htt | N171-82Q | p-eIF2α ↑ | IHC; striatum | Cell death | ||
| Human htt | STHdhQ111/111 | p-PERK ↑ p-eIF2α ↑ ATF4 ↑ CHOP ↑ GADD34↑ |
WB, qPCR | Reduced cytotoxicity | (82) | |
| R6/2 TG mice | p-PERK ↑ p-eIF2α ↑ |
IHC; striatum | Improved motor and executive functions | |||
| ALS | Human SOD1 | SOD1-G93A Tg | p-PERK ↑ p-eIF2α ↑ |
WB, IHC; spinal cord | Motor neuron degeneration | (86) |
| Mutant SOD1 | G93A*SOD1 Tg | PERK ↑ p-eIF2α ↑ CHOP ↑ |
WB; muscle | Muscle atrophy and weakness | (87) | |
| Mutant SOD1 | ATF4−/− -SOD1G86R Tg |
ATF4 ↓ | WB, IHC; spinal cord | Delayed disease onset and prolonged the life span | (88) | |
| Mutant SOD1 | SOD1-G93A Tg | p-eIF2α ↑ | WB; spinal cord | Delayed disease onset and prolonged survival | (89) | |
| Human SOD1 | SOD1-G93A and others | PERK ↓↑ GADD34↓↑ CHOP ↓↑ |
WB, IHC; spinal cord | No effect | (90) | |
| HA-TDP-43 and HA-TDP-43A315T | SH-SY5Y cells | p-eIF2α ↑ CHOP ↑ |
WB | Neuronal toxicity | (97) | |
| Mutant TDP-43 | Flies and rat cortical neuron | p-eIF2α ↑ | WB, IHC | TDP-43 toxicity | (100) | |
| C9orf72 gene | SH-SY5Y cells | CHOP ↑ | WB | Neuronal death | (103) | |
| MS | PERK mutation | C57BL/6 mice with | PERK ↑ p-eIF2α ↑ |
IHC; lumbar spinal cord | Attenuation of disease severity, amelioration of oligodendrocytes loss, demyelination and axon degeneration | (35) |
| IFN-γCNS+; Perk+/+ | ||||||
| PERK transgene | PLP/Fv2E-PERK | (36) | ||||
| PERK knockout | C57BL/6 mice with OL-PERK ko/ko | – | WB, IHC; lumbar spinal cord | Increased oligodendrocytes loss, demyelination and axon degeneration | (37) | |
| Mutant GADD34 | GFAP/tTA; TRE/IFN-γ; GADD34 mice | p-eIF2α ↑ | WB, IHC, EM; brain, lumbar spinal cord | Amelioration of oligodendrocytes loss and hypomyelination | (38) | |
| ATF4 knockout | ATF4loxP/loxP; CNP/Cre mice | WB, IHC; brain, lumbar spinal cord | No effects in oligodendrocytes loss, demyelination, axon degeneration, inflammation and neuron loss | (118) | ||
| PERK inactivation | PERKloxP/loxP; Thy1/CreERT2 mice | – | WB, IHC; brain, lumbar spinal cord | impaired disease resolution and exacerbated EAE-induced axon degeneration, neuron loss and demyelination | (42) | |
| Tumor growth and cancer | Transfection | MCF7, T47D, BT474, BT549, ZR-75-30, Hs578T, MDA-MB-157 and MDA.MB.231 | PERK → | WB, IHC | Cancer invasion and metastasis | (107) |
| – | Melanocytic navi and melanoma | p-eIF2α ↑ | IHC | Cancer initiation and progression | (112) | |
| – | Tumor tissue of breast cancer | p-eIF2α ↑ | IHC | Prognostic tool for breast cancer | (114) | |
| Human osteosarcoma cell | MG63, 143B, KHOS and HOS | p-eIF2α ↓ | WB | Anti-proliferation | (115) | |
| BALB/c-nu mice | PERK ↑ p-eIF2α ↑ CHOP ↑ |
WB, IHC | Decreased tumor growth | (116) | ||
| Human osteosarcoma cell | 143B, SJSA, MG63 and U2OS | |||||
| PERK-deficient | PKO-βTag | – | IHC; pancreata | Reduced proliferation, vascularity, the viability in insulinomas | (119) | |
| Human glioblastoma cell | D54, LN827 | PERK ↑ p-eIF2α ↑ ATF4 ↑ |
WB | Increased cell viability | (122) | |
| glioblastoma cell | LN308, LN229T, NCH82 | PERK ↑ p-eIF2α ↑ |
WB, IF | Regulation of angiogenesis | (124) | |
| Human glioblastoma cell | U87, U251 | ATF4 ↑ | WB, IHC | Promoted tumor angiogenesis | (133) | |
| Transfection | MDA-MB-231 cells | Knockdown of PERK and ATF4 | Transwell and gap closure assay | Reduced migration of breast cancer cell | (130) | |
| Breast cancer | MDA-MB-231 and 468 cells | PERK ↑ p-eIF2α ↑ ATF4 ↑ CHOP↑ |
WB | Apoptotic cell death | (128,137) | |
| Breast cancer | MDA-MB-453, CAL-148, HCC2185 and MFM-223 | PERK ↑ p-eIF2α ↑ ATF4 ↑ |
WB, qRT-PCR | Inhibit androgen receptors activity | (138) | |
| Prostate cancer | LNCap, C4-2 and 22RV1 | |||||
| Human prostate cancer cells | LNCaP, VCaP, 22Rv1 | ATF4 ↑ | WB, IHC | Increased growth and survivability | (135) |
‘↑’ indicates ‘increase"‘↓’ indicates ‘decrease"‘→’ inicates ‘no changes’