PubMed: 25784053

The biology of proteostasis in aging and disease.
Annual review of biochemistry
Labbadia J | Morimoto RI

Evidence c065d7bb8e

Experiments examining the effects of Aβ on proteasomal activity in vitro revealed an inhibitory effect on the chymotrypsin-like properties of the 20S core (73), consistent with observations of impaired proteasome function in AD patient brains (74).

Evidence 6a76e829c1

Reduced levels of lipofuscin, LC3, and p62 have been observed in motor neurons of SOD1(G85R) mice (92). Treatment with the autophagy inhibitor chloroquine restored lipofuscin, LC3, and p62 levels in motor neurons, suggesting that mutant SOD1 causes hyperactive autophagy in mice (92).

Evidence ad613012c4

An in silico screen based on the structure of 10-NCP, an Akt inhibitor that potently induces autophagy (144), identified the molecules FPZ and MTM as potent activators of autophagic flux and clearance of TDP-43 in mammalian cells (145).

Evidence b0e20ed973

One strategy is to directly activate HSF1, thereby increasing the expression of multiple molecular chaperones simultaneously. This approach has been traditionally achieved by inhibition of HSP90 with compounds that bind the N-terminal ATP-binding pocket, such as radicicol, geldanamycin, or 17-AAG (64, 132–134).

Evidence b5c8657199

Treatment of cell, Drosophila, and mouse models of HD, SCA3/MJD, AD, PD, and ALS with the mTOR inhibitor rapamycin (or a derivative) reduces aggregation and suppresses disease (140– 143).

Evidence f27c39fb08

TRiC is essential for proper posttranslational folding of the cytoskeletal components actin and tubulin and is therefore essential for cell structure, division, and cargo delivery (11).

Evidence 1bca54d57e

As discussed above, one approach is to employ specialized molecular chaperone machines to release misfolded proteins from aggregates and direct them to the proteasome for degradation (19).

Evidence 40d96dcf19

. Proteins can be degraded either individually or en masse by proteasomes (20) or lysosomes (21), respectively.

Evidence 9b39d34b8e

Alternatively, bulkier substrates, such as large inclusions, can be directed to the lysosome, a membrane-bound organelle containing a host of nonspecific proteases that can degrade a wide range of substrates (21).

Evidence fae8e2901a

A screen for autophagy inducers in yeast identified the molecules SMER-10, -18, and -28 as TOR-independent activators of autophagy (146).

Evidence 5668c7034e

Treatment of PC12 cells stably expressing mutant α-synuclein (A53T) with SMER-10, -18, or-28 significantly reduced levels of mutant α-synuclein, an effect that was enhanced by cotreatment with rapamycin (146).

Evidence 02ccef1690

In addition, SMER-10, -18, and -28 were effective at suppressing mHTT aggregation and toxicity in COS-7 cells and flies (146).

Evidence 27a7413a7e

High-throughput screens in yeast and HeLa cells identified HSF1A and F1, respectively, as two small molecules that activate HSF1 independently of HSP90 inhibition (136, 137).

Evidence 0d3d4da846

HSF1A suppresses toxicity in cell and tissue culture models of HD and SCA-3/MJD and appears to activate HSF1 by impairing the activity of TRiC, a recently discovered negative regulator of HSF1.

Evidence 44df4d5af9

Treatment with IU1 reduced the levels of Tau, TDP-43, and ataxin-3 in MEFs in a USP14-dependent manner and independently of changes in proteasome levels or composition (147).

Evidence e4a67b2650

ATP hydrolysisis essential for the chaperone activity of HSP70 and HSP90, causing conformational changes that result in substrate binding (11).

Evidence 653c1da1a8

Proteome fidelity is maintained by the protein homeostasis (proteostasis) network (PN), a multi-compartmental system that coordinatesprotein synthesis, folding, disaggregation, and degradation (1).

Evidence 8f4a01b066

Upon increased levels of nonnative proteins, HSF1 is released from its repressive complex, acquires DNA-binding activity through homotrimerization, and rapidly translocates to the nucleus to induce expression of genes encoding molecular chaperones (7, 35).

Evidence fd11c1a732

IRE1 is a transmembrane protein with kinase and endoribonuclease (RNase) activity that senses misfolding in the ER directly, leading to autophosphorylation, oligomerization, and acquisition of RNase activity (8).

Evidence 4c2a692235

Consistent with a role of autophagy in disease, AD patient tissues exhibit impaired initiation of macroautophagy and an excess of autophagic vacuoles in dystrophic neurites, possibly due to impaired targeting of the vacuolar ATPase to the lysosome (86, 87).

Evidence 085a4e0b3f

As such, it is feasible that any reduction in the protein degradation capacity of a cell could contribute to proteostasis collapse and promote aging.

Evidence 81b86ae032

In parallel, ER stress promotes the relocation of ATF6 from the ER membrane to the Golgi apparatus, where it is cleaved by SP1 and SP2 proteases.

Evidence 9276f4bb33

Finally, a third ER transmembrane protein, PERK, promotes translation of the TF ATF4 by phosphorylating the translation initiation factor eIF2α in response to ER stress.

Evidence 123f884a11

HSP60 is essential for maturation and maintenance of the mitochondrial proteome and is therefore intimately linked to energy production.

Evidence 0f37af5ab0

Furthermore, the activity of the PN can be altered permanently or transiently by development and aging, alterations in physiology, or exposure to environmental stress (1).

Evidence 96d573fe45

Additionally, an investigation of chaperone and cochaperone gene expression in young (36±4 years of age) and aged (73 ±4 years of age) human brain tissue revealed that of 332 genes examined, 101 are significantly repressed with age, including HSP70, HSP40, HSP90, and TRiC genes (113). Furthermore, 62 chaperone genes, including several small HSPs, were found to be significantly induced, likely as a result of the cellular response to accumulating protein damage with age (113).

Evidence a73a405d67

Once stress has been relieved, HSF1 activity is repressed through acetylation and binding to molecular chaperones (34, 36, 37).

Evidence 913c4f8a44

Constitutive activation of HSF1 is detrimental to cells and increased expression, and activity of HSF1 has been linked to multiple forms of cancer, highlighting the need for appropriate and balanced activation of stress response pathways as and when required throughout life (122).

Evidence 21851b5445

Perhaps the most significant example of this process is that the HSP110 molecular chaperone, long considered simply a NEF, can catalyze protein disaggregation as part of a complex containing HSP70 and DNAJ/HSP40 (18).

Evidence a7e7972c0d

As such, HSP70 and HSP90 are central to the process of triaging proteins for refolding or elimination.

Evidence 932a4379fe

Furthermore, increased levels of HSP70 were found in the cerebellar cortex of human HD brain samples but not in tissue from unaffected individuals or from brains of PD patients (57).

Evidence 40e75dd19c

Studies of chaperone levels in tissue culture and mouse models of polyQ disease showed that the levels of HSP70 (HSPA1A/B) and DNAJ/HSP40 (DNAJB1), as well as some cochaperones, decline with protein aggregation (64, 65).

Evidence e4a7a3e81c

The cytosolic N-terminal fragment of ATF6 that is generated translocates to the nucleus, binds DNA, and drives expression of a complementary set of UPR genes (8).

Evidence 071bed0020

Under these conditions, ATF4 mRNA is preferentially translated, leading to selective expression of the proapoptotic TF CHOP, which elicits apoptosis if ER stress is not resolved, presumably to ensure that irreversibly damaged cells are removed from the population.

Evidence 12df938d17

Disruption of the ATF6 arm of the UPR(ER) is reported to occur in mouse models of HD and a VAPB cell model of ALS, suggesting that differential changes in UPR arms may be a feature of disease progression (102, 103).

Evidence 06342b7230

Cerebellar granular neurons were found to express high levels of HSP70 in response to mHTT expression but not mAtaxin-1.

Evidence e18f0b2d62

This process allows active IRE1 to cleave XBP1 messenger RNA (mRNA), thereby generating a spliced transcript (XBP1s) that encodes a stable form of XBP1 that binds DNA and induces transcription of UPR target genes (8).

Evidence 535168135c

In contrast, α-synuclein overexpression impairs autophagy in mammalian cells and mice through reduced expression of RAB1A, thereby inhibiting autophagosome formation (88).

Evidence 5ed259cf17

The DUB USP14 suppresses turnover of Tau and TDP-43 in mouse embryonic fibroblasts (MEFs) by impairing the protea-some;

Evidence f73af5c4db

Mice deficient for the autophagy-related genes Atg5 and Atg7 exhibit severe neurodegeneration (84, 85), and the expression of disease- associated proteins is reported to exert differential inhibitory effects on autophagic pathways.

Evidence 36f348e60d

In contrast to findings in HD, AD, and PD, a recent study has suggested that autophagy is enhanced in ALS mice.

Evidence 264857a135

Protein aggregation is recognized as a hallmark of neurodegenerative disease by the consistent appearance of detergent-insoluble inclusions and aggregates in the nucleus and cytoplasm of neurons.


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