Table 1 A list of published C. elegans models of human neurodegenerative diseases and drugs that were shown to confer neuroprotection

Transgenic overexpression of human neurodegeneration-associated protein/peptide

 AD

P _unc-54 ::Aβ _1–42 (wild type); Dimer Aβ _1–42 or Met³⁵Cys Aβ _1–42

CL2005, CL2006, CL1019, CL1118, CL1119, CL1120, CL1121, CL2120; CL2109, CL3109; CL3115

Constitutive muscles

Age-dependent progressive paralysis; forms amyloid deposits; increased oxidative stress

CL2109, CL3109 and CL3115: no formation of amyloid deposits and no increase in oxidative stress

CL2006: caffeine, tannic acid and bacitracin; epigallocatechin gallate; reserpine; Ginkgo biloba extract EGb 761; soya isoflavone glycitein; oleuropein aglycone rifampicin; thioflavin T; curcumin; ferulic acid; fluoxetine; JWB1-84-1 and JAY2-22-33; NT219

CL2120: PBT2

[7, 28, 89–91]

dvIs100 [pCL354(unc-54:DA- Aβ _1–42 ) + pCL26(mtl-2: GFP)].

GMC101

Severe and fully penetrant paralysis within 48 h after temperature shift

PBT2

[31]

smg-1(cc546);Is [P _myo-3 ::Aβ _1–42 ::let UTR) + (rol-6(su1006)]

CL4176

Inducible body wall muscles

Rapid paralysis; oxidative stress precedes amyloid deposition; autophagosome accumulation

Coffee extracts, tetracycline and related analogs; copper; Ginkgo biloba extract EGb 761 and Ginkgolide A and J; Liuwei Dihuang (LWDH); galanthamine; icariside II; cocoa peptide; Carqueja (Baccharis trimera) oleuropein aglycone

[28, 92–95]

smg-1(cc546); Is[P _myo-3 ::GFP::degron + P _mtl-2 ::GFP]

CL2337

Rapid paralysis; formation of stable perinuclear deposits

[96]

smg-1(cc546); Is[P _snb-1 ::Aβ _1-42  + P _mtl-2 ::GFP]

CL2241, CL2355

Inducible pan-neuronal

CL2241 exhibit WT movement. CL2355 is defective in chemotaxis toward benzaldehyde, associative learning, and thrashing in liquid; hypersensitive to serotonin; forms amyloid deposits; has partial sterility due to germline proliferation defects and embryonic lethality

CL2355: Ginkgo biloba extract EGb 761

[15, 96, 97]

N2; Is [P _eat-4 ::ssAβ _1-42 (N-terminus) + P _eat-4 ::gfp + P _myo-2 ::mCherry]

UA166

Glutamatergic neurons

Loss of GFP-marked glutamatergic neurons in an age-related manner; at day 3 only 48 % of worms had five intact glutamatergic neurons, and at day 7 only 25 % did

Clioquinol

[98]

N2; ynIs13[P _snb-1 :APL-1]

N2; ynIs104[P _rab-3 ::apl-1::GFP]

LGIII, LGV, LGX

Constitutive pan-neuronal

Defects in brood size, movement, and viability; severe chemotaxis defects and diminished touch habituation

[99, 100]

 ALS

N2; Is[P _hsp-16.2 ::SOD-1 (WT, A4 V, G37R, G93A) + P _myo-3 ::SOD-1 (WT, A4 V)::GFP + rol-6(su1006)]

Heat shock inducible body wall muscles

Paraquat hypersensitivity; formation of aggregates under oxidative stress

[101]

P _snb-1 ::SOD1(WT,G85R) -YFP

iwIs8gf

Constitutive pan-neuronal

G85R and G85R-YFP: severely reduced forward crawling, thrashings and strong resistance to aldicarb. H46R/H48Q-YFP produced a movement defect less prominent than that seen in G85R-YFP

[102]

N2; Is [P _sng-1 ::SOD-1 (WT, A4 V, G37R, G93C)–EGFP]

Increased aggregation formaton; SOD1(G85R) heterodimeric worms have significantly impaired locomotion and reduced lifespan

[103]

lin -15(n765ts); [P _rgef-1 ::FUS (WT, R514G, R521G, R522G, R524S and P525L) + P _pab-1 :: mcherry; lin-15(+)]

pJH897

Formation of cytoplasmic FUS aggregates; R522G, P525L, FUS513 and FUS501: significantly shorter lifespan. P525L, FUS513 and FUS501: partially or completely paralysed, severely shrunken by 8 days of age

[104]

P _unc-54 ::SOD1(WT, G85R, G93A, G127insTGGGstop)::YFP

AM263; AM265

Constitutive muscles

Accumulation of mutant SOD1 causes 25–30 % decrease in motility on day 2 of adulthood, and further decrease by approx. 10 % on day 6 of adulthood

[105, 106]

unc-119(ed3);Is[P _unc-47 ::TDP-43-(WT, A315T) + unc-119(+)]

unc-119(ed3); Is[P _unc-47 ::FUS-(WT, S57Δ) + unc-119(+)]

xqIs132, xqIs133, xqIs173, xqIs98

GABAergic motor neurons

Have normal lifespan, but displayed adult-onset, age-dependent loss of motility, progressive paralysis, neuronal degeneration, accumulation of highly insoluble TDP-43 and FUS proteins

Methylene blue, salubrinal, guanabenz, and phenazine; resveratrol, rolipram, reserpine, trolox, propyl gallate, and ethosuximide

[62]

[P _snb-1 ::TDP-43-YFP WT(iwIs26)], [P _snb-1 ::TDP-C25-YFP(iwIs22)], [P _snb-1 ::TDP-43-YFP Q331 K(iwEx20)], [P _snb-1 ::TDP-43-YFP M337 V(iwEx28)], [P _snb-1 ::SOD1-YFP WT(iwIs27)] and [P _snb-1 ::SOD1-YFP G85R(iwIs8)]

IW63, IW33, IW20, IW46, IW31, IW8

Constitutive pan-neuronal

Transgenic models developed robust locomotion defects and protein aggregation

[107]

P _unc-25 ::G93A SOD1-GFP

GABAergic motor neurons

Age-dependent paralysis; G93A SOD1 aggregates in neural cell bodies and causes axon guidance defects

[108]

 ALS/FTLD-U

N2; Is[P _snb-1 ::TDP-43 (WT, G290A, A315T, M337 V) + P _snb-1 :GFP]

CK405, CK406, CK410; CK422; CK423; CK426

Constitutive pan-neuronal

Mutant TDP-43: significantly impaired locomotion; degeneration of GABAergic motor neurons

PHA767491; LDN-0130436

[109]

 ALS/FTLD-U

Is[P _unc-25 ::SNB-1::GFP] + Ex[P _snb-1 :TDP-43; P _regf-1 :: DsRed2; P _unc–122 :RFP]

CL2609, CL1681, CL1682

Unc and abnormal motor neuron synapses

[110]

 FTDP-17

N2; Is[P _aex-3 :: 4R1 N human tau (WT, V337 M, P301L) + P _myo-2 ::GFP]

CK10, CK49, CK1301, CK1310

Constitutive pan-neuronal

Mutant tau: strong age-dependent progressive uncoordination and accumulation of insoluble tau; neurodegeneration; presynaptic cholinergic transmission defect; reduced lifespan

Azaperone, clofazimine, isoniazid, lorglumide, nefopam, perphenazine, trazodone, zotepine; ethosuximide

[34, 37, 38]

Pro-aggregant lines: N2; Is[P _rab-3 ::F3ΔK280 + P _myo-2 ::mCherry]

BR5270, BR5485, BR5944, BR5706

Strongly defective locomotion at day 1 of adulthood, accelerated aggregation of insoluble Tau, severe developmental defects of nervous syetem, impaired presynaptic transmission

Methylene blue, BSc3094, bb14 and cmp16

[36]

Anti-aggregant lines: N2; Is[P _rab-3 ::F3ΔK280(I277P)(I308P) + P _myo-2 ::mCherry]

BR5271, BR5486, BR6516, BR6427

No obvious locomotion defects and minimum perturbation of the development of the nervous system

N2; Is [P _mec-7 ::tau WT(0N4R, 0N3R) + rol-6(su1006)]

tmIs82, tmIs83, tmIs84, tmIs85, tmIs171; tmIs110, tmIs173

Touch neurons (ALML/R, AVM, PLML/R, PVM); weak in FLP, PVD, BDU

Age-dependent progressive impairment in touch response; neurodegeneration; tau WT4R: little tau accumulation in PLM neuron

[35]

N2; Is [P _mec-7 :: tau (P301L, R406 W) + rol-6(su1006)]

tmIs81, tmIs178, tmIs179; tmIs146, tmIs147, tmIs148, tmIs149

Strong age-dependent progressive impairment in touch response; neurodegeneration; strong tau accumulation in PLM neuron

pha-1(e2123ts); Ex[P _rgef-1 ::Tau ₃₅₂ (WT, PHP, Ala10) + pha-1(+)]

VH255, VH1016, VH1018; VH254, VH1014, VH1015; VH418, VH421

Constitutive pan-neuronal

Both WT and PHP tau₃₅₂ showed age-dependent progressive uncoordination and neurodegeneration; no change in motor neuron viability. Mutant PHP tau: altered motor neuron development. Ala10 tau: early onset of movement defects and reduced lifespan

[33]

 HD

P _unc-54 ::polyQ-GFP/YFP/CFP

pEGFP-N1-Q19, pEGFP-N1-Q82

Constitutive muscles

Length-dependent formation of aggregates; growth rates slowed down; reduced motility

Icariside II; NG-094; aspirin

[9, 111, 112]

P _unc-54 ::DRPLAP-Q(32, 40, 56, 79)-GFP

pCKX2004, pCKX2003, pCKX2002, pCKX2001

Q > 40: formation of cytoplasmic aggregates

[113]

P _mec-3 ::htt57Q(19, 88, 128)-GFP

P _mec-3 ::htt57Q(19, 88, 128) ::CFP + P _mec-7 :YFP

ID24, ID1

Mechanosensory neurons

Highly penetrant posterior touch insensitivity, significant anterior Mec phenotype; significant deposits and morphological abnormalities in PLM cell axons

Resveratrol

[114, 115]

N2; rmEx[P _rgef-1 ::HttQ (0,19,35,40,67,86)-CFP/YFP]

CFP lines: (Q35) AM303; (Q40) AM305; (Q67) AM308; (Q86) AM313. YFP lines: (Q35) AM78 and AM80; (Q40) AM85 and AM87; (Q67) AM81 and AM83; (Q86) AM322 and AM324

Constitutive pan-neuronal

PolyQ length-dependent aggregation; overt neuronal dysfunction; polyQ length-dependent decrease of thrashing, pharyngeal pumping and erratic defecation cycle

β-Lapachone

[40]

rtIs11[P _osm-10 ::GFP + P _osm-10 ::HttQ150 +Dpy-20(+)]

HA659

Chemosensory neurons

Severe defect in the nose touch response

[41]

pqe-1(rt13) III; rtIs11[P _osm-10 ::GFP + P _osm-10 ::HttQ150 + Dpy-20(+)]

HA759

Accelerated polyQ mediated neurodegeneration. Vast majority (>90 %) of ASH neurons undergo cell death in less than 3 days

Lithium chloride, mithramycin, trichostatin; rotenone, oligomycin and 2,4-dinitrophenol; D. officinarum extracts; salidroside

[42, 43]

N2; rmIs[P _unc-54 ::polyQ(0, 24, 35, 37, 40)::YFP]

(Q35) AM140; (Q37) AM470; (Q40) AM141

Constitutive muscles

Q35 and Q37 aggregation in muscle cells causes a significant motility defect

AM140: ML346; celecoxib; NT219

AM141: salidroside

[106]

 MJD

Full-length ATXN-3 expressing lines: P _rgef-1 ::AT3q14, AT3q75, AT3q130::YFP

AM491, AM513, AM509, AM494, AM519, AM520, AM666, AM685, AM599

Constitutive pan-neuronal

PolyQ length-dependent aggregation and motor dysfunction

17-(allylamino)-17-demethoxygeldanamycin (17-AAG), valproic acid

[116]

C-terminal ATXN-3 expressing lines: P _rgef-1 ::257cAT3q14, 257cAT3q75, 257cAT3q80, 257cAT3q128::YFP

AM396, AM416, AM422, AM391, AM428, AM419, AM420, AM684, AM683, AM702

Worms with truncated ATXN3 expression have similar aggregation profiles in their neurons and have more severe motility defects

N2; [P _unc-54 257cAT3(Q45)::YFP] or P _unc-54 257cAT3(Q63)::YFP

Constitutive muscles

PolyQ length-dependent toxicity; aggregation and toxicity are not significantly modulated by aging

[117]

 PD

N2; Is[P _unc-54 ::α-syn::GFP + rol-6(su1006)]

UA49

Constitutive muscles

α-Syn misfolding and accumulation

[118]

Is[P _unc-54 ::α-syn::YFP + unc-119(+)]

NL5901

Formation of inclusions

10-O-trans-p-Coumaroylcatalpol

[119]

P _aex-3 ::α-syn (WT, A53T) + P _aex-3 ::GFP/P _dat-1 ::GFP

Constitutive pan-neuronal

Motility deficits, significant dopaminergic neuron loss and dendritic breaks

[120]

P _{(acr-2, unc-30)} ::α-syn (WT, A53T) + P _aex-3 ::GFP/P _dat-1 ::GFP

Motor neurons

N2; Is[P _unc-119 ::α-syn (WT, A53T, β-syn) + pDPSU006-GFP]

Constitutive pan-neuronal

A53T: greater vulnerability to rotenone-induced toxicity, exhibiting 68.4 % lower survival after 4 days of 50 μM rotenone treatment

[53]

P _dat-1 ::α-syn (WT, A53T) + P _dat-1 ::GFP

BY273, UA18, UA31, UA44

Dopaminergic neuron

Mean life span was similar among the non-Tg, WT, and A53T α-synuclein-expressing strains; significant DAergic neuron loss and dendritic breaks

Acetaminophen; bromocriptine and quinpirole; valproic acid; spermidine

[120–124]

P _dat-1 ::α-syn (A30P, A53T, A56P) + P _dat-1 ::mCherry

Dopaminergic neuron

Increased neurodegeneration; A30P or A53T: failure in modulation of locomotory rate in response to food and markedly reduced DA content (~1 ng/g vs N2 ~5 ng/g). A56P: more impaired in DA-dependent behaviour

[125]

N2; Is[P _unc-51 ::α-syn (WT, A53T, A30P) + P _unc-51 ::EGFP]

Constitutive pan-neuronal

No motor deterioration or retardation in growth

[126]

N2; Is[P _mec-7 ::α-syn (WT, A53T) + rol-6 (su1006)]

Mechanosensory neurons

Moderate impairments in touch response

P _unc-51 ::S129A or S129D α-syn + P _unc-51 :EGFP

P _unc-51 ::S129A or S129D α-syn + P _unc-25 : SNB-1::GFP

Constitutive pan-neuronal

Strikingly severe motor defects throughout development and aging, growth retardation, and synaptic abnormality. SNB-1::GFP fluorescence was broadly diminished in the nerve cord

[127]

lin-15(n765ts); Is[P _snb-1 ::LRRK2 (WT, G2019S, R1441C, KD, R1441C/KD) + P_mec-4::GFP; lin-15 (+)]

wlzIs1-7

Constitutive pan-neuronal

G2019S LRRK2 increased vulnerability of dopaminergic neurons to mitochondrial stress. Reduced lifespan in mutant LRRK2 (G2019S or R1441C)

[128]

N2; baIn20 [P _dat-1 ::LRRK2 (G2019S) + P _dat-1 ::GFP]

UA118

Dopaminergic neuron

Age-dependent degeneration of DAergic neurons, behavioural deficit, locomotor dysfunction and depletion of dopamine(~72 % loss). G2019S causes more rapid progression of behavioural deficits than others

GW5074, indoline; sorafenib

[60]

BY250; baEx129[P _dat-1 ::LRRK2(G2019S/D1994A)]

UA215, UA216

lin-15(n765ts) X; Is[P _dat-1 ::LRRK2 (WT,R1441C, G2019S, K1347A) + P _dat-1 :GFP + lin-15 (+)]

SGC722, SGC851, SGC856, SGC862

TTT-3002 and LRRK2-IN1

[61, 129]

lin-15(n765ts) X; cwrEx900 [P _dat -1::GFP, P _dat -1::LRRK2(R1441C/A2016T), lin-15(+)]

SG900, SGC910

Double mutants displayed DAergic defects and neurodegeneration similar to R1441C- and G2019S-LRRK2 models.

[61]

 Prion

lin-15(n765ts); [P _mec-7 ::PrP(WT, PG13) + P _Str-1 : GFP; P _mec-7 ::GFP + lin-15 (+)]

Mechanosensory neurons

Progressive loss of response to touch at the tail caused by mutant (PG13-PrP) PrP expression without causing cell death

Quinacrine, resveratrol

[130]

P _ric-19 ::PrP + P _ric-19 ::GFP

cgIs51, cgIs52, cgIs53

Constitutive pan-neuronal

High PrP levels cause abnormal morphology, striking neuropathogenic phenotypes and remarkable reductions in lifespan

[131]

rmIs319[P _unc-54 ::sup35(rΔ2-5, nm, r2e2)::yfp],

AM801, AM803, AM806

Constitutive muscles

Profound cell autonomous and cell non-autonomous disruption of mitochondrial integrity, embryonic and larval arrest, developmental delay, widespread tissue defects, and loss of organismal proteostasis

[132]

Mutant/RNAi

 AD

apl-1(yn10)

Larval lethality, defects in molting and morphogenesis

[133]

apl-1(RNAi)

Reduced body size, with some worms exhibiting L4 molting problems

[99]

sel-12(ar131) and (ar171)

GS1894

Exhibit thermotaxis defects

[134, 135]

 ANCL

dnj-14(ok237)

dnj-14(tm3223)

RM2754

TM3223

Age-dependent progressive impairment in locomotion, severe progressive chemosensory defects which precede neurodegeneration of sensory neurons and significantly shorter lifespan

Resveratrol, rolipram; ethosuximide

[38, 71]

 PD

lrk-1(km17), (km41), (tm1898) and (RNAi)

Mitochondrial stress, ER stress sensitive

[128]

pdr-1(lg103), (XY1046, Parkin KO3) and (RNAi)

Display severe developmental defects and lethality at early larval stages in presence of ER stressors. Majority died or arrested at, or prior to, the larval L3 stage. 15.4 % shorter life span than that of non-Tg strain

[53, 136]

pink-1(tm1779)

Increased sensitivity to a 3-day exposure to 150 mM paraquat

[137]

djr-1.1(RNAi)

Significantly more sensitive to rotenone treatment than control nematodes

[53]

 SMA

smn-1(ok355) I/hT2[bli-4(e937) let-?(q782) qIs48] (I;III)

LM99

Thrashing rate progressively declined and almost completely ceased after 5 days post-L1. Pharyngeal pumping rates showed a rapid and progressive decline. Mean lifespan is 6.0 vs 17.7 days for N2

Riluzole

[138]

smn-1(cb131)I

LL2073

Body length and lifespan was significantly shorter than that of the WT; defective motility, egg-laying and hatching

4-Aminopyridine, gaboxadol hydrochloride, N-acetylneuraminic acid

[77]

Chemical treatment

 PD

vtIs7[P _dat-1 ::GFP] subjected to 6-hydroxydopamine (6-OHDA)

BY250, BY200

Neuronal process blebbing, cell body rounding with process loss and cell body loss reproducibly appear in this order within a few hours

Bromocriptine, quinpirole and memantine; acetaminophen; Chondrus crispus extract

[122, 139–141]

N2; [P _cat-2 ::GFP], egIs1[P _dat-1 ::GFP] subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

BZ555

Reduced mobility, increased lethality and DA neurodegeneration

Lisuride, apomorphine and rottlerin; P7C3, P7C3A20; polysaccharides from Chaenomeles speciosa; acetylcorynoline; n-butylidenephthalide

[54]

N2; [P _dat-1 ::α-syn + P _dat-1 ::GFP] subjected to Manganese (Mn²⁺)

Oxidative stress, mitochondrial stress, enhanced DA neurodegeneration, reduced DA levels

[121]

pink-1(tm1779) subjected to Paraquat

Oxidative stress

[137]

pdr-1(XY1046), P _snb-1 ::α-syn WT, P _unc-119 ::α-syn A53T, N2, lrk-1(km17), P _snb-1 ::LRRK2 (WT, R1441C, G2019S) subjected to Rotenone

Mitochondrial stress, reduced viability

D-α-hydroxybutyrate in combination with tauroursodeoxycholic acid

[53, 128]

P _dat-1 ::GFP subjected to Streptomyces venezuelae secondary metabolite

DA neurodegeneration

[142]