Protein aggregates and proteostasis in aging: Amylin and β-cell function

Press, Michaela; Jung, Tobias; König, Jeannette; Grune, Tilman; Höhn, Annika

doi:10.1016/j.mad.2018.03.010

Cited by 49 publications

(41 citation statements)

References 155 publications

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“…During the aging process, increased oxidative stress leads to a dysfunction of mitochondria and detrimental protein aggregation [37,[40][41][42][43]. Dysfunctional mitochondria and the elevated generation of ROS are among the earliest events occurring in the progression of the numerous neurodegenerative protein aggregation diseases, such as Alzheimer's and Parkinson's diseases [44,45].…”

Section: Discussionmentioning

confidence: 99%

Mitophagy in the Retinal Pigment Epithelium of Dry Age-Related Macular Degeneration Investigated in the NFE2L2/PGC-1α-/- Mouse Model

Gurubaran

Viiri

Koskela

et al. 2020

IJMS

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Increased oxidative stress and mitochondrial damage are observed in protein aggregation diseases, such as age-related macular degeneration (AMD). We have recently reported elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen-like structures in the retinal pigment epithelial cells (RPE) of the dry AMD-resembling NFE2L2/PGC1α double knockout (dKO) mouse model. Here, we provide evidence of a disturbance in the autolysosomal machinery handling mitochondrial clearance in the RPE cells of one-year-old NFE2L2/PGC1α-deficient mice. Confocal immunohistochemical analysis revealed an upregulation of autophagosome marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) as well as numerous mitophagy markers, such as PTE-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN) together with damaged mitochondria. However, we detected no evidence of increased autolysosome formation in transmission electron micrographs or of colocalization of lysosomal marker LAMP2 (lysosome-associated membrane protein 2) and the mitochondrial marker ATP synthase β in confocal micrographs. Interestingly, we observed an upregulation of late autolysosomal fusion Ras-related protein (Rab7) in the perinuclear space of RPE cells together with autofluorescence aggregates. Our results reveal that there is at least a relative decrease of mitophagy in the RPE cells of NFE2L2/PGC1α dKO mice. This further supports the hypothesis that mitophagy is a putative therapy target in AMD-like pathology.

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Section: Discussionmentioning

confidence: 99%

Mitophagy in the Retinal Pigment Epithelium of Dry Age-Related Macular Degeneration Investigated in the NFE2L2/PGC-1α-/- Mouse Model

Gurubaran

Viiri

Koskela

et al. 2020

IJMS

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“…As for IAPP, evidence shows that the ubiquitin-proteosomal system, which includes HSP90, is important for IAPP clearance and turnover. A decline in the function of this system due to inflammation and aging is detrimental to pancreatic islets, allowing IAPP aggregation to occur [94][95][96].…”

Section: Heat Shock Protein 90mentioning

confidence: 99%

Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

Rowles

Keane

Heck

et al. 2020

IJMS

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Type 2 diabetes (T2D) and Alzheimer’s disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar pathological features and underlying mechanisms, including the deposition of amyloidogenic peptides in pancreatic islets (i.e., islet amyloid polypeptide; IAPP) and brain (β-Amyloid; Aβ). Both IAPP and Aβ can undergo misfolding and aggregation and accumulate in the extracellular space of their respective tissues of origin. As a main response to protein misfolding, there is evidence of the role of heat shock proteins (HSPs) in moderating T2D and AD. HSPs play a pivotal role in cell homeostasis by providing cytoprotection during acute and chronic metabolic stresses. In T2D and AD, intracellular HSP (iHSP) levels are reduced, potentially due to the ability of the cell to export HSPs to the extracellular space (eHSP). The increase in eHSPs can contribute to oxidative damage and is associated with various pro-inflammatory pathways in T2D and AD. Here, we review the role of HSP in moderating T2D and AD, as well as propose that these chaperone proteins are an important link in the relationship between T2D and AD.

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“…Since ubiquitine‐proteasome system (UPS) and autophagy‐lysososme pathway (ALP) are essential to maintain proteostasis, they strongly influence cellular fate and consequently the aging process. UPS process determines not only the recognition and subsequent degradation of oxidized and dysfunctional proteins, but it is also involved in the degradation of functional ones, while the ALP is able to recognize and incorporate principally protein aggregates (Press, Jung, Konig, Grune, & Hohn, in press). Notably, even if misfolded proteins are directed to these degrading systems in order to prevent their neurotoxicity, the intrinsic pathogenic property of these aggregates causes a secondary inhibition of the proteasome as well as lysosome system leading to further aggregation and cell death (Manecka, Vanderperre, Fon, & Durcan, ; Vijayakumaran & Pountney, ).…”

Section: Molecular Alterations Occurring In Agingmentioning

confidence: 99%

Brain aging: A Ianus‐faced player between health and neurodegeneration

Vanni

Baldeschi

Zattoni

et al. 2019

J of Neuroscience Research

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Neurodegenerative diseases are incurable debilitating disorders characterized by structural and functional neuronal loss. Approximately 30 million people are affected worldwide, and this number is predicted to reach more than 150 million by 2050. Neurodegenerative disorders include Alzheimer’s, Parkinson’s, and prion diseases among others. These disorders are characterized by the accumulation of aggregating proteins forming amyloid, responsible for the disease‐associated pathological lesions. The aggregation of amyloidogenic proteins can result either in gaining of toxic functions, derived from the damage provoked by these deposits in affected tissue, or in a loss of functions, due to the sequestration and the consequent inability of the aggregating protein to ensure its physiological role. While it is widely accepted that aging represents the main risk factor for neurodegeneration, there is still no clear cut‐off line between the two conditions. Indeed, many of the pathways that are commonly altered in neurodegeneration—misfolded protein accumulation, chronic inflammation, mitochondrial dysfunction, impaired iron homeostasis, epigenetic modifications—have been often correlated also with healthy aging. This overlap could be explained by the fact that the continuous accumulation of cellular damages, together with a progressive decline in metabolic efficiency during aging, makes the neurons more vulnerable to toxic injuries. When a given threshold is exceeded, all these alterations might give rise to pathological phenotypes that ultimately lead to neurodegeneration.

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Protein aggregates and proteostasis in aging: Amylin and β-cell function

Cited by 49 publications

References 155 publications

Mitophagy in the Retinal Pigment Epithelium of Dry Age-Related Macular Degeneration Investigated in the NFE2L2/PGC-1α-/- Mouse Model

Mitophagy in the Retinal Pigment Epithelium of Dry Age-Related Macular Degeneration Investigated in the NFE2L2/PGC-1α-/- Mouse Model

Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

Brain aging: A Ianus‐faced player between health and neurodegeneration

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