PubMed: 30116051

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.
Nature reviews. Drug discovery
Boland B | Millan MJ | Bezard E | Corti O | Duchen MR | Eskelinen EL | Henriques A | Kroemer G | Levine B | Louis C | Mallucci GR | Martin OR | Mochel F | Mollereau B | Nixon RA | Pastores GM | Rubinsztein DC | Spedding M | Yu WH

Evidence 60b901cac6

Second, the TFEB inducer 2-hydroxypropyl-β-cyclo- dextrin promoted the acidity of lysosomes in neurons 190 .

Evidence 6605c484c2

In regard to pharmacological manipulation, substances such as epigallocatechin and somatostatin promote the expression, secretion and (allosterically) catalytic activ- ity of IDE and neprilysin in parallel with an increase in the degradation of Aβ peptides 259,280 .

Evidence 80c7e100a6

Indeed, clioquinol countered disruption of autophagy by chloroquine in retinal cells, reduced Aβ42 accumulation in CHO cells expressing APP and mutant presenilin 1 and diminished amyloid misfolding and aggregation in Tg2576 AD mice 196,197 .

Evidence 2bfa02b5e2

The aminoimidazole derivative 5-aminoimidazole- 4-carboxamide ribonucleotide (AICAR) undergoes intra- cellular transformation to an AMP analogue that triggers AMPK-mediated autophagy 21,108 .

Evidence c3efd3831c

In addition, calcitriol (the active metabolite of vitamin D 3 ) elicited AMPK-dependent autophagy in a neurochemical lesion-induced model of PD 129.

Evidence 7eaa91ff19

Because the class III deacetylase NAD- dependent protein deacetylase sirtuin 1 (SIRT1) requires nicotinamide adenine dinucleotide (NAD) to sustain its activity, this positive regulator of autophagy may also be considered a sensor 24 .

Evidence dd66d657a8

SIRT1 is activated by AMPK- mediated increases in nicotinamide, and it drives the ALN by inhibiting mTORC1, inducing FOXO1 and FOXO3 and activating key regulatory proteins such as ATG5, ATG7 and LC3.

Evidence 3018298de2

The di-glucose derivative trehalose inhibits the sol- ute carrier 2A (SLC2A) family of glucose transporters to promote AMPK-induced autophagy and reduce neurotoxic protein load, although it also exerts other actions downstream in the ALN 4,120 .

Evidence de07729779

It also proved effective in cellu- lar models of PD, HD and AD 121,122 , as well as in mouse models of HD, AD and tauopathies, where it cleared aggregates, reduced neurodegeneration and ameliorated motor and cognitive performance 123–125 .

Evidence 964d1ef97d

Sixth, Aβ42 compro- mises the function of AMPK to impede initiation of the ALN 67 .

Evidence 0ff21f916e

Seventh, Aβ42 obstructs the UPS and CMA 47,68 .

Evidence 8beed3c8f9

The UPS and CMA are disrupted by neurotoxic proteins like Aβ42 and tau, hence, their early and preventive reinforcement prior to Aβ42 and tau accumulation may be critical.

Evidence 8945c6d390

The microtubule stabilizers paclitaxel and epothilone A countered Aβ42-induced cytoskeletal disruption — and moderated excessive UPR — in neurons 182 .

Evidence 1770905df0

In a vicious circle, Aβ42 itself decreases IDE expression, although it may prompt its release from glia 254,259 .

Evidence 965e2193b1

Furthermore, epothilone D countered microtubule disruption and cognitive deficits in aged P301S/P19 AD mice 183 .

Evidence b843c4e076

Lithium ions inhibit inositol monophosphatase to deplete inositol triphosphate.

Evidence 25f0fad81d

This mechanism may be involved in its promotion of autophagy, reduction in cel- lular levels of α-synuclein, SOD1, Htt and tau 126 , ame- lioration of motor function in a P301L mouse model of tauopathy 127 and slowing of disease progression in SOD1 mice 128 .

Evidence 117b783b3a

For example, methylene blue coun- ters tau oligomerization and promotes autophagy 101,102 (Supplementary Table 4).

Evidence 68b7193096

Other compounds that act through AMPK acti- vation include the antiaggregant methylene blue (Supplementary Box 1), which elevated levels of beclin  1, p62 and LC3, induced autophagy and suppressed tau in organotypic neuronal cultures and a mouse model of FTD 101,102 .

Evidence 7e69838899

Third, acidic nanoparticles such as polylactic acid and poly(lactide- co-glycolide) increase acidification (BOX 3) .

Evidence 92392f3575

Selenium deficits have been linked to AD, and thus it is interesting that seleno- methionine boosted ALN flux, from AMPK recruit- ment through autophagosome formation to lysosomal degradation, in the 3×Tg AD mouse model 112 .

Evidence 337cce02cb

Calpeptin, a cell-permeable calpain inhibitor, can also reduce Htt proteinopathy via induction of autophagy 103,105 .

Evidence 37932477d3

In addition, the plant-derived alkaloid isorhynchophylline upregulated beclin 1 independently of mTORC1 and promoted autophagic clearance of α-synuclein, although its precise mechanism of action remains to be clarified 175 .

Evidence 4c808a1dc8

Indeed, clonidine and rilmenidine, two G i /G o -coupled α 2 -adrenergic receptor and imidazoline 1 receptor agonists, stimulate autophagy and cleared Htt in cellular 103 and animal models of HD 104 .

Evidence ae192b19c7

Likewise, temsirolimus reduced the accumulation of phosphorylated tau in SH-SY5Y cells and P301S tauopathy mice 137 .

Evidence 2875168f88

It also removed cellular aggregates of mutant Htt and improved motor performance in a mouse model of HD, reduced α-synuclein aggregation and afforded neuroprotection in a lesion-based model of PD and depleted mutant ataxin 3 in a mouse model of supraspinal cerebellar ataxia type 3 (REFS133,138,139) .

Evidence 04949e8fc1

It increased expression of βGCase, normalized autophagy and accelerated degradation of α-synuclein in a stem cell model of dopaminergic neurons derived from patients with PD bearing mutations in βGCase 200 .

Evidence 8e82c62887

Ambroxol, which also decreased ER stress in D. mela- nogaster 201 , reduced α-synuclein levels in overexpress- ing, transgenic mice 202 .

Evidence 2384e25456

Cilostazol (a phosphodiesterase 3 inhibitor) clears Aβ42 from neuronal cell lines by promoting autophagy, upregulating beclin 1, ATG5 and LC3, downregulating mTORC1 and inducing lysosomal cathepsin B; these actions of cilostazol involve activation of SIRT1 as well as upstream Tyr172 phosphorylation of AMPK 108,162,163 .

Evidence 25ea3229ed

Cilostazol improved cognition and reduced levels of Aβ42 and hyperphosphorylated tau following intra- cerebroventricular injection of Aβ25–35 into mice 162,163 .

Evidence f517b9078c

The natural product curcumin induced macro- autophagy and protected rotenone-treated dopaminer- gic neurons 141 in addition to accelerating the elimination of mutant α-synuclein-A53T by repressing mTORC1 in a cellular model of early-onset PD, although it also exerts other actions such as inhibition of p300-mediated pro- tein acetylation and of aggregation 142,143 .

Evidence 5b2236f8dc

Pro-autophagic effects of curcumin are reflected in improved function in cellular and animal models of PD and AD, as well as reduced levels of α-synuclein aggregates 144 or Aβ and tau oligomers 145,146 .

Evidence be0af7325d

Moreover, the flavonol fisetin stimulated auto- phagic degradation of phosphorylated tau in cortical neu- rons via mTORC1-dependent activation of TFEB and the cytoprotective transcription factor nuclear factor eryth- roid 2-related factor 2 (NFE2L2) 149 . Fisetin also reduced Aβ accumulation in an APP/PS1 mouse model of AD 150 .

Evidence f13048d024

Among compounds that inhibit HSP90, geldanamycin promoted elimination of both hyper- phosphorylated tau and oligomeric α-synuclein in cell lines 219,220 .

Evidence f278d8f987

The antidiabetic drug metformin, a prototypical activator of AMPK, induced autophagy and increased longevity in mice 116 .

Evidence be09b6ad5b

Moreover, reductions in levels of hyper phosphorylated tau and Aβ were seen in metformin- treated neurons 117,118 , while it blunted neuronal loss in a neurochemical lesion model of PD in mice 119 .

Evidence 7e259dd7fe

Inactivation of ABL1 with brain-penetrant nilotinib conferred neuroprotective autophagy in mouse models of PD 153 .

Evidence db0989afb6

The ‘anti-ageing’ agent resveratrol is thought to indi- rectly recruit AMPK via activation of calcium/calmodulin- dependent protein kinase kinase 2 (CAMKK2), which, acting in synergy with Ca 2+ , exerts its effects via Thr172 phosphorylation 113 . This action, among others (below), is involved in its reduction of Aβ levels in N2a cells and neurons 114 and the elimination of Aβ and Htt in animal models of AD and HD 114,115 .

Evidence 55f87335b6

Resveratrol can stimulate SIRT1 via AMPK (see above), and it also possesses an AMPK-independent mode of SIRT1 recruitment that participates in blunting the neurotoxicity of Aβ25–35 fragments in PC12 cells 160 .

Evidence d14a83b1b0

The multi-modal agent resveratrol induced the expression of ATG4 and promoted autophagosome formation.

Evidence a90083f7eb

Interestingly, resver- atrol downregulated RAGE as well as MMP9 — an effect that is related to decreased hippocampal load of Aβ42 (REF.297) .

Evidence 11528ab402

The antibiotic rifampicin likewise promoted Aβ42 clearance by induc- ing BBB-localized LRP1 and P glycoprotein 1 (REFS273,292) .

Evidence d17c8e5d29

Enhancing auto- phagy with rapamycin reduced levels of α-synuclein, FUS and Htt 130–132 .

Evidence 4700b0a723

Spermidine inhibits the acetylation of ATG7 and histone H3, while induc- ing beclin 1 via blockade of its cleavage by caspase 3 (REF.168) .

Evidence f27d7fc24a

The less cytotoxic analogue of geldanamycin, 17-AAG, has improved brain penetrance. It decreased Aβ levels 223 , improved memory 224 and lowered tau in transgenic AD mice 224 . 17-AAG also reduced α-synuclein oligomers in H4 cells 220 .

Evidence f6ef14af5d

Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 .

Evidence 35b8b0ec32

Finally, while physiological tau possesses KFERQ motifs and is degraded by CMA, aggregates, mutant forms and frag- ments interfere with CMA 45,47 .

Evidence a5d88a4394

Sixth, aggregates and mutant forms of α-synuclein disrupt the proteasome in dopaminergic neurons.

Evidence 70c22f9e66

Third, apolipoprotein E allele 4 (APOE4), a major risk allele for sporadic AD, is associated with increased generation and accumula- tion of Aβ42 (REFS59,60) .

Evidence 3376eece4f

In addition to decreased degradation, one consequence is leakage of asparaginyl endopeptidase into the cytosol, where it generates toxic fragments of tau 61 .

Evidence 2b4921b600

Harnessing TFEB by 2-hydroxypropyl-β-cyclodextrin promoted clearance of proteolipid aggregates and α-syn- uclein in a cellular model of PD 195,204 .It also augmented the elimination of Aβ in a Tg19959/CRND8 mouse model of AD 173 .

Evidence 3f90c121de

An unusual approach to augmenting autophagosome formation is represented by the brain- penetrant autophagy enhancer 99 (AUTEN-99), which blocks myotubularin-related protein 14 (MTMR14, also known as Jumpy), a phosphatase that inhibits the phos- phoinositide 3-kinase (PI3K)-mediated generation of the autophagosome membrane (FIG. 3) . AUTEN-99 aug- mented autophagic flux in isolated neurons, increased markers of autophagy in mouse brain and slowed neuro- degeneration in D. melanogaster models of PD and HD 181 .

Evidence d68097faf9

Fourth, activation of the lysosomal Ca 2+ channel mucol- ipin transient receptor potential channel 1 (TRPML1) with a synthetic agonist (ML-SA1) increased lysoso- mal Ca 2+ release, lowered pH and promoted Aβ clear- ance 191,192 .

Evidence ffd21e45f1

Chronic administration of CGS-21680, a selective agonist of the AC-coupled adenosine A 2A receptor, restored proteasomal activity in cellular and murine models for HD via PKA-mediated Ser120 phosphorylation of the RPT6 component of the 19S subunit 231 .

Evidence 7cb828fa9b

Another HSP90 inhibitor, HSP990, has shown promise in lowering Htt aggregates and improving motor performance in two mouse models of HD 225 .

Evidence e2ba775a53

Another direct facilitator of AMPK, A769662, elicited autophagy and reduced the burden of Htt in a striatal cell line derived from knock-in mice expressing a humanized form of mutant Htt (exon 1 containing seven polyglutamine repeats) 111 .

Evidence fa776aff5a

One promising agent is the hydroxylamine deriva- tive arimoclomol, which increases the activity of HSP70 by augmenting transcriptional activity of HSF1 (REF.210) .

Evidence 79e2990071

Tau, α-synuclein and TDP43 are substrates for CMA degradation, as are amyloid precursor protein (APP) but not amyloid-β fragment 42 (Aβ42) itself 3,45–47,48 .

Evidence 8a13b5e343

CMA dysfunction in PD favours the accumulation of α- synuclein and leads to inactivation of the dopaminergic neuron survival factor, myocyte-specific enhancer factor 2D (MEF2D) 2,45,47,55 .

Evidence b648e7840b

Htt is not efficiently cleared by CMA, and the same appears to hold for its fragments and mutant and post- translationally modified forms, although the precise role of CMA in Htt elimination remains to be more fully defined 2,45–47 .

Evidence 4b86bad9a5

Interestingly, the UPS is important for elimination of tau and other neurotoxic proteins in post synaptic dendritic compartments (a key site of spreading), where it plays a more general role favouring synaptic plasticity, den- dritogenesis and memory formation 49,52 .

Evidence 27288b8b17

Activity of the deacetylase SIRT1 declines with age, partially owing to limited availability of its co fac- tor, nicotinamide 24,56,156 .

Evidence cd75217283

Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 .

Evidence 9e2bf480fc

Mutant Htt is cleared by autophagy, but it compromises the ALN because of decreased cargo load- ing and impaired autophagosome formation and trans- port 55,56,68,92 .

Evidence 6d42282938

Some of these lead to an impairment of the ALN owing to reduced activation of beclin 1; another repercussion may be altered process- ing of APP, providing an unexpected link to AD 69,71–73 .

Evidence 5735147d3b

This kinase is classically inactivated by rapamycin, which binds to the modulatory protein 12 kDa FK506-binding protein (FKBP12; also known as FKBP1A).

Evidence 73b9a8c1ea

Disruption of this Bcl-2–beclin 1 complex is an alternative approach for promoting autophagy, as achieved in mouse fibroblasts by the BH3 mimetic ABT-737 (REF.177) .

Evidence ecd3667992

Activation of ULK1 triggers autophagosome nucleation through activating phospho- rylation of AMBRA and beclin 1 within the autophagy- specific PIK3C3 complex 10 (FIG. 3) .

Evidence 224737d83a

Third, cellular inhibitor of apoptosis 1 (CIAP1; also known as BIRC2) specifically binds mutant SOD1 and drives it to proteasomal degradation.

Evidence 401f44fada

Another kinase that activates the proteasome (RPT6 subunit) — and directs it to dendritic spines — is CAMKK2 (REF.227) .

Evidence 665186c04b

Fifth, mutations in APP similarly disrupt endosomal and lysosomal func- tion, in part owing to accumulation of the β-secretase- generated, carboxy-terminal and Aβ42-containing fragment of APP called C99 (REF.66) .

Evidence 8aea6da98d

The heterotrimeric serine/threonine kinase 5ʹ‑AMP‑ activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) trigger autophagy and repress mitophagy 3,10,20–23 (BOX 2; FIG. 3) .

Evidence fae977b7f9

AMPK is central to several mechanisms that trigger autophagy — most importantly, activating phosphoryla- tion of ULK1 (Ser317 and Ser777) and inhibitory phos- phorylation of mTORC1 (REFS21,31) .

Evidence 8d493a81d8

One major strategy for promoting autophagy is the relief of its repression by mTORC1.

Evidence 92fa3cf46b

Conversely, mTORC1 inhibits ULK1 by Ser757 phosphorylation 3,4,31 .

Evidence 51dd7b8c02

mTORC1 also restrains autophagy by preventing nuclear translo- cation of TFEB 20 .

Evidence 550585f147

Finally, mirroring its inhibitory influence on the ALN, mTORC1 suppresses the UPS by impeding the formation and assembly of proteasomal subunits.

Evidence 828652e5d2

Tyrosine-protein kinase ABL1 is a proto- oncogene that negatively regulates autophagy, partly acting upstream of the RAC serine/threonine-protein kinase (AKT)–mTORC1 axis.

Evidence 5695f0ca97

Activation of aquaporin 4 channels on perivascular astrocytes to aid the glymphatic elimination of cerebral Aβ and other toxic proteins is a potential strategy for stimulating clearance.

Evidence 9e396cd025

However, in light of common risk genes such as SQSTM1 (which encodes p62) and chromosome 9 open reading frame 72 (C9ORF72), FTD is increasingly linked to ALS 82,83 .

Evidence ffa57082c3

Mutations in C9ORF72 (the most prevalent risk gene for familial ALS and FTD) are likewise linked to disruption of the ALN, including interference with dynactin–dynein coordinated transport of autophagosomes along axons of motor neurons to the perikarya 82,88 .

Evidence 0426d9b52b

Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 .

Evidence c441686683

Calpain inhibition by cal- pastatin or pharmacological agents also confers neuropro- tective effects in other NDA models, including improved clearance of tau, α-synuclein and SOD1 (REFS54,106,107) .

Evidence 88dad808f4

ALS shares many causal genes with FTD, including SQSTM1, CHMP2B, TBK1 (which encodes tank-binding kinase 1), OPTN (which encodes optineurin) and other genes associated with deficits in ALN and mitophagy.

Evidence c656fe45fa

Other transcription factors that posi- tively regulate autophagy include forkhead box protein O1 (FOXO1) and FOXO3 (REF.22) .

Evidence 9fcf403b20

Fourth, homozygous mutations of lyso- somal β-glucocerebrosidase (βGCase; also known as GBA) provoke the LSD Gaucher disease, which is linked to decreased ALN flux, α-synuclein accumulation and a fivefold increase in risk of PD 43 (Supplementary Box 1).

Evidence aca74ea92d

Furthermore, expression of progranulin in the hippocampus of AD mice reduces the density of amyloid plaques by enhanc- ing the activity of neprilysin 281 .

Evidence c69a9d6404

Aβ42 and amylin (a pancreas-derived, AD-associated protein found in brain) are substrates for degradation by IDE, which also irreversibly traps Aβ42 and α-synuclein, preventing their aggregation and promoting ALN and UPS elimination 259 .

Evidence 1574a8205b

IDE also degrades and prevents the forma- tion of α-synuclein fibrils 259 .

Evidence 4d02efdc38

Finally, the extracellular and intracellular serine protease neurosin (also known as KLK6) cleaves α- synuclein.

Evidence 2ab2ebca2b

Nonetheless, overexpression of LAMP2A accelerated CMA-related clearance of α-synuclein and afforded pro- tection of dopaminergic neurons 45 , and several routes to potential pharmacological exploitation exist.

Evidence 2ca01b27ca

Second, the GTPase leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) is the most commonly mutated protein in late-onset, familial PD.

Evidence cf72a67cf3

In addition, CMA is disrupted by sev- eral genetic mutations occurring in PD, including muta- tions in LRRK2 (REFS2,3,45–47,55,69,80) .

Evidence 178f1a75be

Similar to IDE, neprilysin catabolizes Aβ42, and its loss in mouse models of AD and in patients with AD alike also contributes to Aβ42 accumulation 253,256,260 .

Evidence dd7c810a8c

For example, mutations in OPTN and TBK1 interfere with cargo loading 82,84,87 .

Evidence c91716b74e

First, autosomal recessive forms of early-onset PD are associated with mutations in PTEN-induced putative kinase protein 1 (PINK1) and the E3 ubiquitin-protein ligase parkin; these mutations lead to deficits in the mitophagic removal of damaged mitochondria 69,70 (BOX 2) .

Evidence 80b154482b

Like IDE and neprilysin, plasmin degrades Aβ42 and blocks Aβ42-induced toxicity, suggesting that the decrease in its levels in AD is involved in the evolution of AD 254,256,261 .

Evidence 0670afa4e0

Plasmin also degrades α-synuclein to retard intercellular spreading 262 .

Evidence fda632430d

Furthermore, mutations in the gene encoding parkin and several other genes are linked to reduced UPS activity 2,56,69,79,80 .

Evidence 1757b77227

Interestingly, genetic or pharmacological activation of RAB5 countered neurodegeneration in mouse C9ORF72 models of ALS and FTD 187 .

Evidence 26bc6e63a9

Supporting the relevance of sestrin 2, it has been shown to protect dopaminergic neurons from the neurotoxin rotenone via AMPK-transduced autophagy 247 .

Evidence f744b49d6b

Sestrin 2 over expression also prompted mTORC1-dependent autophagy in cortical neurons in a presenilin-knockout model of AD.

Evidence 45b67644f6

Third, α-synuclein mutations, triplications or excesses amplify the ALN burden, interfere with auto phagosome formation and irreversibly disrupt the lysosomal mem- brane 1,3,44,56 .

Evidence 48eb990d0a

Conversely, repression is effected by signal transducer and activator of transcrip- tion 3 (STAT3) and possibly zinc-finger protein with KRAB and SCAN domains 3 (ZKSCAN3), although its role has been disputed 22,32 .

Evidence 0182fd3dc2

Unc-51-like kinase 1 (ULK1) is primarily an autophagy-initiating protein 3,10,19 , as is the mTORC1- suppressed transcrip- tion factor EB (TFEB), which orchestrates the synthesis of lysosomal and other proteins critical for maintaining ALN flux 20–23 .

Evidence aad7da9b2d

Indeed, TFEB over- expression reduced amyloid plaques in a APP/PS1 mouse model 148 .

Evidence 0806b93dcb

Second, while decr1eases in beclin 1 levels in AD remain to be confirmed, SIRT1 expression is diminished 24 .

Evidence e9dfb7a488

ABL1 is overactivated in AD and tauopathies such as FTD 152 .

Evidence 5ca1153e9b

Cerebral levels of IDE are reduced in early AD and in mouse models of AD, whereas, mirroring AD amyloidosis, Aβ42 accumulates in mice genetically depleted of IDE.


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