Protein Homeostasis in Models of Aging and Age-Related Conformational Disease

Aging is characterized by a gradual deterioration in proteome. However, how protein dynamics that changes with normal aging and in disease is less well understood. Here, we profiled the snapshots of aging proteome in Drosophila, from head and muscle tissues of post-mitotic somatic cells, and the testis of mitotically-active cells. Our data demonstrated that dysregulation of proteome homeostasis, or proteostasis, might be a common feature associated with age. We further used pulsed metabolic stable isotope labeling analysis to characterize protein synthesis. Interestingly, this study determined an age-modulated decline in protein synthesis with age, particularly in the pathways related to mitochondria, neurotransmission, and proteostasis. Importantly, this decline became dramatically accelerated in Pink1 mutants, a Drosophila model of human age-related Parkinson's disease. Taken together, our multidimensional proteomic study revealed tissue-specific protein dynamics with age, highlighting mitochondrial and proteostasis-related proteins. We suggest that declines in proteostasis and mitochondria early in life are critical signals prior to the onset of aging and aging-associated diseases.

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Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21218014 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8014

Author(s):

Sudip Dhakal ◽

Ian Macreadie

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stress Responses ◽

Cell Biology ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Yeast Cells ◽

Yeast Genome ◽

Protein Homeostasis ◽

Age Related

Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. The loss of proteostasis is one of the major causes of AD: it is evident by aggregation of misfolded proteins, lipid homeostasis disruption, accumulation of autophagic vesicles, and oxidative damage during the disease progression. Different models have been developed to study AD, one of which is a yeast model. Yeasts are simple unicellular eukaryotic cells that have provided great insights into human cell biology. Various yeast models, including unmodified and genetically modified yeasts, have been established for studying AD and have provided significant amount of information on AD pathology and potential interventions. The conservation of various human biological processes, including signal transduction, energy metabolism, protein homeostasis, stress responses, oxidative phosphorylation, vesicle trafficking, apoptosis, endocytosis, and ageing, renders yeast a fascinating, powerful model for AD. In addition, the easy manipulation of the yeast genome and availability of methods to evaluate yeast cells rapidly in high throughput technological platforms strengthen the rationale of using yeast as a model. This review focuses on the description of the proteostasis network in yeast and its comparison with the human proteostasis network. It further elaborates on the AD-associated proteostasis failure and applications of the yeast proteostasis network to understand AD pathology and its potential to guide interventions against AD.

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Targeting the Mitochondria-Proteostasis Axis to Delay Aging

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.656201 ◽

2021 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Andreas Zimmermann ◽

Corina Madreiter-Sokolowski ◽

Sarah Stryeck ◽

Mahmoud Abdellatif

Keyword(s):

Quality Control ◽

Therapeutic Potential ◽

Human Life ◽

Molecular Targets ◽

Protein Homeostasis ◽

Novel Therapies ◽

Pharmacological Interventions ◽

Mitochondrial Quality Control ◽

Age Related ◽

Organ Systems

Human life expectancy continues to grow globally, and so does the prevalence of age-related chronic diseases, causing a huge medical and economic burden on society. Effective therapeutic options for these disorders are scarce, and even if available, are typically limited to a single comorbidity in a multifaceted dysfunction that inevitably affects all organ systems. Thus, novel therapies that target fundamental processes of aging itself are desperately needed. In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.

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Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

Open Biology ◽

10.1098/rsob.200296 ◽

2021 ◽

Vol 11 (4) ◽

Author(s):

Anna Ainslie ◽

Wouter Huiting ◽

Lara Barazzuol ◽

Steven Bergink

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Neurodegenerative Diseases ◽

Genome Stability ◽

Genome Instability ◽

Copy Number Variations ◽

Therapeutic Interventions ◽

Gene Copy ◽

Protein Homeostasis ◽

Age Related

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

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SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

Frontiers in Pharmacology ◽

10.3389/fphar.2020.585821 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ramu Manjula ◽

Kumari Anuja ◽

Francisco J. Alcain

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Histone Deacetylases ◽

Neurological Diseases ◽

Clinical Manifestations ◽

Life Extension ◽

Protein Homeostasis ◽

Brain Functions ◽

Age Related ◽

And Function

Sirtuins are NAD+ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.

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A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing

Nature Communications ◽

10.1038/s41467-019-12821-2 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Yifei Zhou ◽

Xueqing Wang ◽

Mengjiao Song ◽

Zhidong He ◽

Guizhong Cui ◽

...

Keyword(s):

Quality Control ◽

Caenorhabditis Elegans ◽

Extracellular Vesicles ◽

Body Wall ◽

Protein Quality ◽

Protein Quality Control ◽

The Body ◽

Protein Homeostasis ◽

Age Related ◽

Different Tissues

Abstract Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83/miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans. Upregulated in the intestine by hsf-1/HSF1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5/MCOLN, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity. These findings thus identify a microRNA-based mechanism to coordinate the decreasing macroautophagy in various tissues with age.

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Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Cells ◽

10.3390/cells9102183 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2183

Author(s):

Tuuli-Maria Sonninen ◽

Gundars Goldsteins ◽

Nihay Laham-Karam ◽

Jari Koistinaho ◽

Šárka Lehtonen

Keyword(s):

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Inflammatory Responses ◽

Biological Response ◽

Protein Damage ◽

Protein Homeostasis ◽

Cellular Functions ◽

Regenerative Capacity ◽

Age Related ◽

Lateral Sclerosis

Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.

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Age-related loss of hepatic Nrf2 protein homeostasis: Potential role for heightened expression of miR-146a

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2015.11.003 ◽

2015 ◽

Vol 89 ◽

pp. 1184-1191 ◽

Cited By ~ 19

Author(s):

Eric J. Smith ◽

Kate P. Shay ◽

Nicholas O. Thomas ◽

Judy A. Butler ◽

Liam F. Finlay ◽

...

Keyword(s):

Potential Role ◽

Protein Homeostasis ◽

Age Related ◽

Nrf2 Protein

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Mitochondrial Impairment in Sarcopenia

Biology ◽

10.3390/biology10010031 ◽

2021 ◽

Vol 10 (1) ◽

pp. 31

Author(s):

Francesco Bellanti ◽

Aurelio Lo Buglio ◽

Gianluigi Vendemiale

Keyword(s):

Skeletal Muscle ◽

Muscle Quality ◽

Protein Homeostasis ◽

Related Condition ◽

Selective Autophagy ◽

Mitochondrial Homeostasis ◽

Mitochondrial Alterations ◽

Mitochondrial Impairment ◽

Age Related ◽

And Function

Sarcopenia is defined by the age-related loss of skeletal muscle quality, which relies on mitochondrial homeostasis. During aging, several mitochondrial features such as bioenergetics, dynamics, biogenesis, and selective autophagy (mitophagy) are altered and impinge on protein homeostasis, resulting in loss of muscle mass and function. Thus, mitochondrial dysfunction contributes significantly to the complex pathogenesis of sarcopenia, and mitochondria are indicated as potential targets to prevent and treat this age-related condition. After a concise presentation of the age-related modifications in skeletal muscle quality and mitochondrial homeostasis, the present review summarizes the most relevant findings related to mitochondrial alterations in sarcopenia.

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Drosophila p38 MAPK Interacts with BAG-3/starvin to Regulate Age-dependent Protein Homeostasis

10.1101/552729 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sarah M. Ryan ◽

Michael Almassey ◽

Amelia M. Burch ◽

Gia Ngo ◽

Julia M. Martin ◽

...

Keyword(s):

Protein Aggregation ◽

P38 Mapk ◽

Protein Aggregates ◽

Protein Homeostasis ◽

Selective Autophagy ◽

Age Related ◽

Age Dependent ◽

Dependent Protein ◽

Locomotor Behaviors ◽

The Relationship

SummaryAs organisms age, they often accumulate protein aggregates that are thought to be toxic, potentially leading to age-related diseases. This accumulation of protein aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of genetic factors have been linked to longevity, but how these factors also contribute to protein homeostasis is not completely understood. In order to understand the relationship between aging and protein aggregation, we tested how a gene that regulates lifespan and age-dependent locomotor behaviors, p38 MAPK (p38Kb), influences protein homeostasis as an organism ages. We find that p38Kb regulates age-dependent protein aggregation through an interaction with the Chaperone-Assisted Selective Autophagy complex. Furthermore, we have identified Lamin as an age-dependent target of p38Kb and the Chaperone-Assisted Selective Autophagy complex.

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