Introduction
Review
Clinical manifestation and epidemiology of amyotrophic lateral sclerosis
Classical ALS
Bulbar ALS
Fronto-temporal dementia
Epidemiology
Neuropathology
Diagnostic criteria
Mutation in familial cases of ALS
Superoxide dismutase 1 (SOD1)
Mutation | Mean age at onset (y ± SD) | Site at onset | Survival (yr ± SD) | Clinical manifestations | References | |||
---|---|---|---|---|---|---|---|---|
UMN | LMN | Cognitive symptoms | Neuropathological findings | |||||
A4V | 47.8 ± 13.3 | Limbs | 1.4 ± 0,9 | Mild | Y, Pred | N | LBHI, NCI | |
G37R | 40.0 ± 9.9 | Limbs | 18.7 ± 11.4 | Y | Y | N | LBHI | |
H46R | 49.6 ± 10.9 | Legs | 17.3 ± 10.7 | Y | Y, Pred | N | LBHI | |
H48Q | 54 | nd | 8 months | nd | Y, Pred | nd | LBHI,SLI | |
L84V | 53.8 ± 15.3 | Arms | 1.6 ± 0.5 | Y | Y, Pred | N | nd | |
D83G | 55 | Legs | 6 | Y | Y, Pred | N | nd | [46] |
G85R | nd | nd | nd | nd | nd | nd | nd | [43] |
D90A | 44 | Legs | 13 | Y | Y | nd | nd | |
G93A | 47.4 ± 12.4 | Limbs | 10.0 ± 6.2 | nd | nd | N | nd | |
I113T | 58.9 ± 12.6 | Limbs | 3.5 ± 2.8 | nd | Y, pred | Y | NFT, ICAI, HC, NFCI | |
L126Z | 58 | nd | 4 | nd | Y | nd | LBHI | |
G127X | 50 | Limbs | 2.8 | Y | Y | nd | nd | [242] |
Species | Mutation | Age at onset (weeks) | Survival (weeks) | Phenotype | References | |||
---|---|---|---|---|---|---|---|---|
Paralysis | Cognitive symptoms | Neuropathological findings and particularities | Gliosis | |||||
Mice | hSOD1WT
| 58–70 | normal | N | nd | Mitochondria vacuolization and swelling,, spinocerebellar axonal degeneration, 20-30 % MN loss | Y | [69] |
hSOD1WT
| 36 | 52 | Y | nd | SOD1 inclusions, vacuolization, MN loss, glial cell aggregates | Y | [71] | |
A4V | >85 | normal | N | N | nd | N | [70] | |
A4V/SOD1WT
| 35 | 48 | Y | nd | SOD1 inclusions, MN degeneration | Y | [70] | |
G37R | 15–17 | 25–29 | Y | Learning deficit | MBV, LMN first affected, raised somatosensory thresholds | Y | ||
H46R | 20 | 24 | Y | nd | LBHI, ubiquitin, SOD1 inclusions | Y | [244] | |
H46R/H48Q | 17–26 | nd | Y | nd | HI, ubiquitin | nd | [245] | |
H46R/H48Q/ | 35–52 | nd | Y | nd | Fibrillary SOD1-ubiquitin inclusions | Y | [246] | |
H63G/H120G | ||||||||
D83Ga
| 15 | 70–84 | N | nd | Sensory deficit, tremors, 20 % LMN and UMN loss | Y | [78] | |
L84V | 21–26 | 26–30 | Y | nd | nd | nd | [247] | |
G85R | 35–43 | 37–45 | Y | nd | Rapid progression, SOD1-ubiquitin inclusions in neurons and astrocytes | Y | [248] | |
G85R/SOD1WT
| 16–21 | 23–30 | Y | nd | SOD1 aggregates | Y | [249] | |
G86Rb
| 13–17 | 17 | Y | nd | Rapid progression (5 days) | nd | [250] | |
D90A | 52 | 61 | Y | nd | Distended bladder, SOD1 inclusions, MN loss | Y | [75] | |
G93A | 13–17 | 17–26 | Y | Y | MN loss, SOD1 aggregates, NMJ loss before onset | Y | ||
G93A/SOD1WT
| 20–23 | 25–30 | Y | nd | Vacuoles, MN loss | Y | [69] | |
Thy1.2-G93Ac
| 54- >104 | 62- >104 | N | nd | SOD1 aggregates | Y | [79] | |
L126Z | 28–44 | 47 | Y | nd | Eosinophilic inclusion, MN loss, ubiquitin inclusions | Y | ||
G127X | 35 | 36 | Y | nd | Rapid disease course, SOD1-ubiquitin inclusions | Y | [252] | |
Rats | H46R | 20 | 24 | Y | nd | MN loss, LBHI, SOD1-ubiquitin aggregates | Y | [253] |
G93A | 16 | 17 | Y | nd | MN loss, vacuoles, SOD1-ubiquitin inclusions | Y | ||
Dogs | T18S | 7 years | 21 monthsd
| Y | nd | SOD1 aggregates No neuronal cell body loss, UMN and LMN signs, sensory impairment | Y | [86] |
E40K | >5 years | 6 months–3 yearsd
| Y | nd | Y | [85] | ||
Zebrafish | A4Ve
| 30 h | nd | N | nd | Motor axonopathy and abnormal branching | nd | [90] |
G37Re
| 30 h | nd | N | nd | nd | [90] | ||
G93Ae
| 30 h | nd | N | nd | nd | [90] | ||
G93A | 20–60 | nd | N | nd | Increase time resting but no swim speed change, NMJ loss, 50 % MN loss | nd | [91] | |
G93Rf
| 12 months | 18–27 months | partial | nd | NMJ defects, MN loss, swimming incapacity, vacuolated mitochondria | nd | [92] | |
Fruit flies | hSOD1WT
| 3 | normal | N | nd | Loss of climbing, no MN loss, decrease synaptic transmission in giant fiber motor pathway | HSP70 stress response | [93] |
A4V | 4 | normal | N | nd | [93] | |||
G85R | 2 | normal | N | nd | [93] | |||
D83S | 4 | normal | N | nd | Mitochondrial pathology, decreased physical activity | nd | [255] | |
Nematodes | hSOD1WT
| 10 days | 10–20 D | Y | nd | Reduction in thrash number | nd | [95] |
G85R | 10 days | 10–20 D | Y | nd | Forward movement defect, SOD1 inclusions | nd | [95] | |
G93A | 2 days | nd | Y | nd | SOD1 inclusions in MN, axons guidance defects | nd | ||
C6S/C57S/ | normal | normal | N | nd | No phenotype | nd | [95] | |
C111S/C146S | ||||||||
Pigs | G93A | 12 | normal | N | nd | MN loss at 8 months, Intra-nuclear SOD1-ubiquitin inclusions, running deficit, fibrillation potentials and positive sharp waves at EMG | Y | [99] |
TAR-DNA-binding protein (TDP-43)
Mutation | Age at onset (years ± SD) | Site at onset | Survival (months ± SD) | Clinical manifestations | References | |||
---|---|---|---|---|---|---|---|---|
UMN | LMN | Cognitive symptoms | Neuropathological findings | |||||
G287S | 62.3 ± 9.3 | Bulbar, Spinal | 76 ± 15.4 | Y | Y | N | ||
G290A | 49.5 ± 2.1 | Bulbar, Spinal | 12a
| Y | Y | N | [123] | |
G298S | 50.7 ± 6.2 | Bulbar, Spinal | 27.0 ± 11.1 | Y | Y | N | Bunina bodies, gliosis, neuronal loss anterior horn, NCI, GCI | |
A315T | 65.5 ± 13.6 | Spinal | 109.7 ± 32.3 | Y | Y | N | Gliosis, spinal neuronal loss, NCI, neurofibrillary tangles, Aβ deposit | |
Q331Kb
| 72 | Spinal | 36 | nd | nd | nd | [122] | |
M337V | 47.7 ± 8.8 | Bulbar, Spinal | 105.0 ± 59.6 | Y | Y | N | NCI, GCI, Bunina bodies | |
G348C | 46.4 ± 10.7 | Spinal | 81.3 ± 37 | Y | Y | Apathy, anxiety | ||
A382T | 51.3 ± 8.6 | Bulbar, Spinal | 58.1 ± 44.4 | Y | Y | Dementia | ||
N390Dc
| 53 | Spinal | 35 | Y | Y | N | [121] |
Species | Mutation | Promoter (fold expression) | Age at onset (weeks) | Survival (weeks) | Phenotype | References | |||
---|---|---|---|---|---|---|---|---|---|
Paralysis | Cognitive symptoms | Neuropathological findings and particularities | Gliosis | ||||||
Mice | hTDP-43WT
| mPrp (3–4) | None | Normal | N | nd | Diffuse ubiquitin staining, no NCI | mild | [262] |
mPrp (2.5)
a
|
3
|
4–8
|
Y
|
nd
|
pTDP-43 NCI, cytosolic ubiquitination, axonal degeneration, no MN loss
|
Y
| [135] | ||
mThy1.2(3.8–5.1) | 2–8 | 4–27 | Y | nd | Rapid disease progression, rare pTDP-43 NCI, MN loss, phenotype correlates with protein level | Y | [263] | ||
mThy1.2(1.3–3.6) | Males: 2 Females: 13 | nd | nd | nd | Mitochondrial aggregation, no TDP-43 NCI, decreased axon caliber, no MN loss | nd | [264] | ||
mCaMKIIc (0.4–1.7) | 4 | nd | nd | nd | Brain atrophy, Neuron loss, mosaic expression, rare pTDP-43 NCI | Y | [265] | ||
CAG | None | Normal | N | nd | No motor impairment, neuron loss in frontal cortex, no NCI | nd | [266] | ||
hEP (3) | 42 | Normal | N | Y | No TDP-43/ubiquitin NCI, motor dysfunction without paralysis | Y | [138] | ||
mTDP-43WT
| mCaMKII(2)a
| 8 | 71 | N | Y | Learning/memory deficit, TDP-43/ubiquitin positive NCI, progressive motor deficits | Y | [267] | |
A315T\ | mPrp (4) | 4 | 10.7 | Y | nd | Rare pTDP-43 NCI, no GCI, MA | Y | [134] | |
mPrp (3)
|
12–16
|
22 ± 2.7
|
Y
|
nd
b
|
Ubiquitin positive/TDP-43 negative NCI, UMN/LMN loss
|
Y
| [139] | ||
hEP (3)
|
38
|
Normal
|
N
|
Y
|
TDP-43+/Ubiquitin + NCI at 10 months, peripherin inclusions, decrease axonal caliber, motor dysfunction without paralysis
|
Y
| [138] | ||
mEP (2.5)d
| nd | nd | nd | N | TDP-43 NCI, 10 % MN loss | nd | [268] | ||
Q331K | mPrp (1.5) | 12 | Normal | N | nd | Decreased motor performance at 10 months, muscle fibrillations at EMG, No NCI | Y | [140] | |
WT/Q331K
|
mPrp (3.3)
|
3
|
8–10
|
Y
|
nd
|
TDP-43/ubiquitin/p62 NCI, 70 % MN loss in SC anterior horn
|
Y
| [141] | |
M337V | mPrp (2.7)a
| 3 | 4 | Y | nd | Tremors, pTDP-43 NCI, cytosolic ubiquitination, no MN loss, MA | Y | [269] | |
mPrp (1.5) | 40 | Normal | N | nd | Decreased motor performance at 10 months, no NCI | nd | [140] | ||
Thy1.2 (1.7)a
| <2 | 2,5 | Y | nd | Ubiquitin/TDP-43 NCI, worse phenotype than TDP-43WT mouse | Y | [270] | ||
G348C
|
hEP (3)
|
36
|
Normal
|
N
|
Y
|
TDP-43+/Ubiquitin+ NCI at 10 months, peripherin inclusions, decreased axonal caliber, motor dysfunction without paralysis
|
Y
| [138] | |
Rats | hTDP-43WT
| hEP (nd) | Normal | Normal | N | nd | Normal | nd | [142] |
M337V | hEP (nd) | 2–3 | 1.5–4 | Y | nd | Loss of MN in ventral horn | nd | [142] | |
M337V | TRE (nd) PN day 4 | 3 | 5 | Y | nd | Degeneration of ventral root, dorsal root and corticospinal tract, pTDP-43 staining, but no NCI | Y | [142] | |
TRE-NFH(nd) PN day 60 | 10 | nd | Y | nd | Paralysis within 3 weeks, no TDP-43 NCI, motor function restores with removal of TDP-43 | Y | [143] | ||
TRE-GFAP(1.3) PN day 40 | 8.6 | 11.4 | Y | nd | MN loss, MA, | nd | [271] | ||
Fruit flies | hTDP-43WT
| OK371-Gal4e (nd) | 10 days | nd | N | nd | TDP-43 inclusions, MN loss, larval motility deficit | nd | [272] |
D42-Gal4e(nd) | 2–3 | 2.5–3.5 | Y | nd | Progressive motor deficit leading to paralysis, no NCI | nd | [145] | ||
GAL4-UAS(nd) | nd | nd | Y | nd | Dose-dependent cytosolic TDP-43 and NCI, decreased larvae and adult movement, decreased NMJ | nd | [148] | ||
WT, Q331K | MN (nd) | nd | nd | nd | nd | Motor deficits, Q331K had worst phenotype | nd | [273] | |
WT, F147L/F149L, G287S, A315T, G348C, A382T, ΔNLS | D42-Gal4e(nd) | 10–20 days | 20–40 days | Y | nd | Progressive loss of motor performance, worse phenotype seen in WT, MN loss | nd | [146] | |
dTDP-43 | D42TS-Gal4f(nd) | 12–14 days | 23 days | N | nd | Decreased thoracic number of neurons, locomotor defect, shorter lifespan | nd | [147] | |
Nematodes | TDP-1, hTDP-43WT | snb-1 | larvae | nd | N | nd | No NCI, slow movement | nd | [149] |
hTDP-43WT, G290A, A315T, M337V | snb-1 | nd | 13–18.9 days | Y | nd | Lethargy, flattened sinusoidal waveform and reduced locomotion, worse phenotype with mutations, pTDP-43, ubiquitin, no NCI, nuclear aggregates | nd | [150] | |
hTDP-43WT, A315T | unc-47 | 4–6 days | normal | Y | nd | GABAergic motor neurons expression, older paralysis in WT (20 days) as compared to A315T (12–13 days), MN loss, cytoplasmic TDP-43 | nd | [207] | |
Zebrafish | hTDP-43WT, A315T, G348C, A382T | mRNAs | 24 hpf | nd | Y | nd | Motor deficit, phenotype was mRNA concentration dependant, worse phenotype in mutant, decreased motor axons length | nd | [151] |
hTDP-43WT, A315T | mRNAs | 28 hpt | nd | nd | nd | Reduced axonal length in A315T | nd | [152] |
C9ORF72
Species | Number of repeats | Promoter | Age at onset (weeks) | Survival (weeks) | Phenotype | References | |||
---|---|---|---|---|---|---|---|---|---|
Paralysis | Cognitive symptoms | Neuropathological findings and particularities | Gliosis | ||||||
Mice | 80 | TRE | none | normal | N | N | ubiquitin-positive inclusion, no DPR, no TDP-43 inclusion | nd | [174] |
66a
| nd | 24 | nd | nd | Y | Nuclear RNA foci, phosphoTDP-43 inclusions, cytosolic and nuclear DPR, Anxiety and social abnormalities, motor impairment | Y | [176] | |
100–1000 | BACb
| none | normal | N | N | RNA foci, DPR, no NCI | N | [178] | |
500 | BACb
| none | normal | N | N | RNA foci, DPR, no NCI | N | [177] | |
450 | BACb
| 52 | normal | N | Y | RNA foci, DPR, age-dependant protein accumulation, no motor deficits or MN loss, age dependant cognitive deficit, no TDP-43 mislocalization | N | [179] | |
500 | BACb
| 16 | 20–40c
| Y | Y | NMJ loss, reduced axonal size, MN loss, RNA foci, DPR, TDP-43 NCI | Y | [180] | |
Fruit flies | 36–103 | elav-GS | nd | 30 days | nd | nd | RNA foci, DPR, toxicity was attributed to DPR | nd | [182] |
160 | actin5C-Gal4 | none | normal | N | nd | RNA foci, DPR, toxicity was attributed to DPR | nd | [181] | |
30 | Ok371-Gal4 | 4 | nd | nd | nd | Decreased locomotor activity | nd | [183] | |
58 | Ok371-Gal4 | nd | nd | nd | nd | Decreased locomotor activity, NMJ loss, DPR | nd | [184] | |
Nematodesd
| n/a | alfa-1 | 2 | nd | Y | nd | MN loss, paralysis in 60 % of worms | nd | [185] |
Zebrafishe
| n/a | n/a | nd | nd | nd | nd | MN axons shortening, reduced swimming | nd | [186] |
Fused in sarcoma (FUS)
Species | Mutation | Promoter | Age at onset (days) | Survival (days) | Phenotype | References | |||
---|---|---|---|---|---|---|---|---|---|
Paralysis | Cognitive symptoms | Neuropathological findings and particularities | Gliosis | ||||||
Mice | KO | n/a | nd | nd | nd | nd | 24 h death, chromosomal abnormality, sterility | nd | [198] |
KO | n/a | nd | nd | nd | Y | No motor phenotype, hyperactivity behavior | nd | [199] | |
hFUSWT
| mPrp | 4 weeks | 10–13 weeks | Y | N | Tremors, weight loss, deficit in rotarod, increase cytoplasmic FUS signal, spinal MN loss, NMJ loss | Y | [200] | |
hFUSWT, R521G | CAG | 10 | 30 | Na
| Y | More lethality in FUSWT, no MN loss in lateral column, MA, NMJ loss, reduced social interaction and motor performance | Y | [201] | |
Rats | hFUSWT, R521Cb
| TRE | 27–48 | 33–55 | Y | Y | Few MN loss, MA, NMJ loss, ubiquitin inclusions, no FUS inclusions | Y | [202] |
Fruit flies | hFUSWT, R524S, P525L | OK371-Gal4 | nd | nd | nd | nd | Large MN, decreased locomotor function, NMJ loss | nd | [203] |
hFUSWT, R518K, R521C, R521H | OK371-Gal4/elav-GS | 10 | ~17 | nd | nd | Decreased locomotor function, no NMJ loss, more cytosolic FUS in mutant, | nd | [204] | |
Nematodes | hFUSWT, R514G, R521G, R522G, P525L, FUS513, FUS501 | Prgef-1
| 3 | 8.1–9.7 | Y | nd | NCI of mutant FUS, worst phenotype in R522G, P525L, FUS513 and FUS501 | nd | [206] |
S57Δ |
unc-47 | 12–13 | normal | Y | nd | MN loss, FUS insoluble aggregates | nd | [207] | |
Zebrafish | R521C, R521H, S57Δ | mRNA | 48 hpf | nd | nd | nd | Reduced swimming at TEER, NMJ loss | nd |