scholarly journals Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process

2008 ◽  
Vol 29 (4) ◽  
pp. 1095-1106 ◽  
Author(s):  
Ayako Tonoki ◽  
Erina Kuranaga ◽  
Takeyasu Tomioka ◽  
Jun Hamazaki ◽  
Shigeo Murata ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Life Span ◽  
Cellular Protein ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Loss Of Function ◽  
Ubiquitinated Proteins ◽  
Age Related ◽  
Age Dependent ◽  
Progressive Neurodegeneration

ABSTRACT The intracellular accumulation of unfolded or misfolded proteins is believed to contribute to aging and age-related neurodegenerative diseases. However, the links between age-dependent proteotoxicity and cellular protein degradation systems remain poorly understood. Here, we show that 26S proteasome activity and abundance attenuate with age, which is associated with the impaired assembly of the 26S proteasome with the 19S regulatory particle (RP) and the 20S proteasome. In a genetic gain-of-function screen, we characterized Rpn11, which encodes a subunit of the 19S RP, as a suppressor of expanded polyglutamine-induced progressive neurodegeneration. Rpn11 overexpression suppressed the age-related reduction of the 26S proteasome activity, resulting in the extension of flies' life spans with suppression of the age-dependent accumulation of ubiquitinated proteins. On the other hand, the loss of function of Rpn11 caused an early onset of reduced 26S proteasome activity and a premature age-dependent accumulation of ubiquitinated proteins. It also caused a shorter life span and an enhanced neurodegenerative phenotype. Our results suggest that maintaining the 26S proteasome with age could extend the life span and suppress the age-related progression of neurodegenerative diseases.

scholarly journals Early-Onset Parkinson Disease Screening in Patients From Nigeria

2021 ◽  
Vol 11 ◽  
Author(s):  
Lukasz M. Milanowski ◽  
Olajumoke Oshinaike ◽  
Benjamin J. Broadway ◽  
Jennifer A. Lindemann ◽  
Alexandra I. Soto-Beasley ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Parkinson Disease ◽  
Neurodegenerative Diseases ◽  
Early Onset ◽  
Local Population ◽  
Age At Onset ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
African Countries ◽  
Age Related

Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S.Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset <50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted.Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function.Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.

scholarly journals Age-dependent degeneration of an identified adult leg motor neuron in a Drosophila SOD1 model of ALS

Biology Open ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. bio049692
Author(s):  
Anthony Agudelo ◽  
Victoria St. Amand ◽  
Lindsey Grissom ◽  
Danielle Lafond ◽  
Toni Achilli ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Gene Replacement ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Age Related ◽  
Disease Mutations ◽  
Discs Large ◽  
Age Dependent ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis

ABSTRACTMutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS) in humans. ALS is a neurodegenerative disease characterized by progressive motor neuron loss leading to paralysis and inevitable death in affected individuals. Using a gene replacement strategy to introduce disease mutations into the orthologous Drosophila sod1 (dsod1) gene, here, we characterize changes at the neuromuscular junction using longer-lived dsod1 mutant adults. Homozygous dsod1H71Y/H71Y or dsod1null/null flies display progressive walking defects with paralysis of the third metathoracic leg. In dissected legs, we assessed age-dependent changes in a single identified motor neuron (MN-I2) innervating the tibia levitator muscle. At adult eclosion, MN-I2 of dsod1H71Y/H71Y or sod1null/null flies is patterned similar to wild-type flies indicating no readily apparent developmental defects. Over the course of 10 days post-eclosion, MN-I2 shows an overall reduction in arborization with bouton swelling and loss of the post-synaptic marker discs-large (dlg) in mutant dsod1 adults. In addition, increases in polyubiquitinated proteins correlate with the timing and extent of MN-I2 changes. Because similar phenotypes are observed between flies homozygous for either dsod1H71Y or dsod1null alleles, we conclude these NMJ changes are mainly associated with sod loss-of-function. Together these studies characterize age-related morphological and molecular changes associated with axonal retraction in a Drosophila model of ALS that recapitulate an important aspect of the human disease.This article has an associated First Person interview with the first author of the paper.

scholarly journals Relative Structural and Functional Roles of Multiple Deubiquitylating Proteins Associated with Mammalian 26S Proteasome

2008 ◽  
Vol 19 (3) ◽  
pp. 1072-1082 ◽  
Author(s):  
Elena Koulich ◽  
Xiaohua Li ◽  
George N. DeMartino
Keyword(s):  
Cell Growth ◽  
Protein Degradation ◽  
Mammalian Cells ◽  
Cellular Protein ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Detectable Effect ◽  
Functional Roles ◽  
Functional Relationships ◽  
Proteolytic Capacity

We determined composition and relative roles of deubiquitylating proteins associated with the 26S proteasome in mammalian cells. Three deubiquitylating activities were associated with the 26S proteasome: two from constituent subunits, Rpn11/S13 and Uch37, and one from a reversibly associated protein, Usp14. RNA interference (RNAi) of Rpn11/S13 inhibited cell growth, decreased cellular proteasome activity via disrupted 26S proteasome assembly, and inhibited cellular protein degradation. In contrast, RNAi of Uch37 or Usp14 had no detectable effect on cell growth, proteasome structure or proteolytic capacity, but accelerated cellular protein degradation. RNAi of both Uch37 and Usp14 also had no effect on proteasome structure or proteolytic capacity, but inhibited cellular protein degradation. Thus, proper proteasomal processing of ubiquitylated substrates requires Rpn11 plus either Uch37 or Usp14. Although the latter proteins feature redundant deubiquitylation functions, they also appear to exert noncatalyic effects on proteasome activity that are similar to but independent of one another. These results reveal unexpected functional relationships among multiple deubiquitylating proteins and suggest a model for mammalian 26S proteasome function whereby their concerted action governs proteasome function by linking deubiquitylation to substrate hydrolysis.

scholarly journals Platelet Proteasome Activity and Metabolism Is Upregulated during Bacterial Sepsis

2019 ◽  
Vol 20 (23) ◽  
pp. 5961 ◽  
Author(s):  
Katharina Grundler Groterhorst ◽  
Hanna Mannell ◽  
Joachim Pircher ◽  
Bjoern F Kraemer
Keyword(s):  
Platelet Function ◽  
Cellular Protein ◽  
Proteasome Activity ◽  
Bacterial Sepsis ◽  
Proteasome Activator ◽  
E Coli ◽  
Ubiquitinated Proteins ◽  
First Time ◽  
Vital Element

Dysregulation of platelet function can contribute to the disease progression in sepsis. The proteasome represents a critical and vital element of cellular protein metabolism in platelets and its proteolytic activity has been associated with platelet function. However, the role of the platelet proteasome as well as its response to infection under conditions of sepsis have not been studied so far. We measured platelet proteasome activity by fluorescent substrates, degradation of poly-ubiquitinated proteins and cleavage of the proteasome substrate Talin-1 in the presence of living E. coli strains and in platelets isolated from sepsis patients. Upregulation of the proteasome activator PA28 (PSME1) was assessed by quantitative real-time PCR in platelets from sepsis patients. We show that co-incubation of platelets with living E. coli (UTI89) results in increased degradation of poly-ubiquitinated proteins and cleavage of Talin-1 by the proteasome. Proteasome activity and cleavage of Talin-1 was significantly increased in α-hemolysin (HlyA)-positive E. coli strains. Supporting these findings, proteasome activity was also increased in platelets of patients with sepsis. Finally, the proteasome activator PA28 (PSME1) was upregulated in this group of patients. In this study we demonstrate for the first time that the proteasome in platelets is activated in the septic milieu.

scholarly journals ZFAND5/ZNF216 is an activator of the 26S proteasome that stimulates overall protein degradation

2018 ◽  
Vol 115 (41) ◽  
pp. E9550-E9559 ◽  
Author(s):  
Donghoon Lee ◽  
Shinichi Takayama ◽  
Alfred L. Goldberg
Keyword(s):  
Protein Degradation ◽  
Zinc Finger ◽  
Mouse Embryonic Fibroblast ◽  
Cellular Protein ◽  
26S Proteasome ◽  
Peptidase Activity ◽  
Protein Breakdown ◽  
Proteasomal Activity ◽  
Ubiquitinated Proteins ◽  
Proteasome Regulators

ZFAND5/ZNF216, a member of the zinc finger AN1-type domain family, is abundant in heart and brain, but is induced in skeletal muscle during atrophy (although not in proteotoxic stress). Because mice lacking ZFAND5 exhibit decreased atrophy, a role in stimulating protein breakdown seemed likely. Addition of recombinant ZFAND5 to purified 26S proteasomes stimulated hydrolysis of ubiquitinated proteins, short peptides, and ATP. Mutating its C-terminal AN1 domain abolished the stimulation of proteasomal peptidase activity. Mutating its N-terminal zinc finger A20 domain, which binds ubiquitin chains, prevented the enhanced degradation of ubiquitinated proteins without affecting peptidase activity. Mouse embryonic fibroblast (MEF) cells lacking ZFAND5 had lower rates of protein degradation and proteasomal activity than WT MEFs. ZFAND5 addition to cell lysates stimulated proteasomal activity and protein degradation. Unlike other proteasome regulators, ZFAND5 enhances multiple 26S activities and overall cellular protein breakdown.

Age-dependent decline in 26S proteasome activity in Drosophila

2007 ◽  
Vol 42 (1-2) ◽  
pp. 147-148
Author(s):  
V.A. Vernace ◽  
Lisette Arnaud ◽  
T. Schmidt-Glenewinkel ◽  
M.E. Figueiredo-Pereira
Keyword(s):  
Proteasome Activity ◽  
26S Proteasome ◽  
Age Dependent

scholarly journals Antioxidants Enhance Mammalian Proteasome Expression through the Keap1-Nrf2 Signaling Pathway

2003 ◽  
Vol 23 (23) ◽  
pp. 8786-8794 ◽  
Author(s):  
Mi-Kyoung Kwak ◽  
Nobunao Wakabayashi ◽  
Jennifer L. Greenlaw ◽  
Masayuki Yamamoto ◽  
Thomas W. Kensler
Keyword(s):  
Antioxidant Response ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Proximal Promoter ◽  
Protective Effects ◽  
Protein Levels ◽  
Age Related ◽  
Nrf2 Signaling Pathway ◽  
Antioxidant Response Elements ◽  
Indirect Action

ABSTRACT Proteasomes degrade damaged proteins formed during oxidative stress, thereby promoting cell survival. Neurodegenerative and other age-related disorders are associated with reduced proteasome activity. We show herein that expression of most subunits of 20S and 19S proteasomes, which collectively assemble the 26S proteasome, was enhanced up to threefold in livers of mice following treatment with dithiolethiones, which act as indirect antioxidants. Subunit protein levels and proteasome activity were coordinately increased. No induction was seen in mice where the transcription factor Nrf2 was disrupted. Promoter activity of the PSMB5 subunit of the 20S proteasome increased with either Nrf2 overexpression or treatment with antioxidants in mouse embryonic fibroblasts. Tandem antioxidant response elements in the proximal promoter of PSMB5 that controlled these responses were identified. We propose that induction of the 26S proteasome through the Nrf2 pathway represents an important indirect action of these antioxidants that can contribute to their protective effects against chronic diseases.

scholarly journals Trigonelline Extends the Lifespan of C. Elegans and Delays the Progression of Age-Related Diseases by Activating AMPK, DAF-16, and HSF-1

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Wen-Yu Zeng ◽  
Lin Tan ◽  
Cong Han ◽  
Zhuo-Ya Zheng ◽  
Gui-Sheng Wu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Neurodegenerative Diseases ◽  
Stress Resistance ◽  
Aging Effect ◽  
Loss Of Function ◽  
Asian Countries ◽  
C Elegans ◽  
Age Related ◽  
Anti Oxidant ◽  
Pathogenic Effects

Trigonelline is the main alkaloid with bioactivity presented in fenugreek, which was used in traditional medicine in Asian countries for centuries. It is reported that trigonelline has anti-inflammatory, anti-oxidant, and anti-pathogenic effects. We are wondering whether trigonelline have anti-aging effect. We found that 50 μM of trigonelline had the best anti-aging activity and could prolong the lifespan of Caenorhabditis elegans (C. elegans) by about 17.9%. Trigonelline can enhance the oxidative, heat, and pathogenic stress resistance of C. elegans. Trigonelline could also delay the development of neurodegenerative diseases, such as AD, PD, and HD, in models of C. elegans. Trigonelline could not prolong the lifespan of long-lived worms with loss-of-function mutations in genes regulating energy and nutrition, such as clk-1, isp-1, eat-2, and rsks-1. Trigonelline requires daf-16, hsf-1, and aak-2 to extend the lifespan of C. elegans. Trigonelline can also up-regulate the expression of daf-16 and hsf-1 targeted downstream genes, such as sod-3, gst-4, hsp-16.1, and hsp-12.6. Our results can be the basis for developing trigonelline-rich products with health benefits, as well as for further research on the pharmacological usage of trigonelline.

scholarly journals When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 740 ◽  
Author(s):  
Patrycja Michalska ◽  
Rafael León
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Energy Demand ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
High Energy ◽  
Antioxidant Defenses ◽  
Loss Of Function ◽  
Age Related ◽  
The Brain

Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions. Driven by age-related changes, neurodegeneration is characterized by increased oxidative stress leading to irreversible neuronal damage, followed by cell death. Nevertheless, neurodegenerative diseases are known as complex pathologies where several mechanisms drive neuronal death. Herein we discuss the interplay among oxidative stress, proteinopathy, and neuroinflammation at the early stages of neurodegenerative diseases. Finally, we discuss the use of the Nrf2-ARE pathway as a potential therapeutic strategy based on these molecular mechanisms to develop transformative medicines.

scholarly journals Ocular Neurodegenerative Diseases: Interconnection between Retina and Cortical Areas

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2394
Author(s):  
Nicoletta Marchesi ◽  
Foroogh Fahmideh ◽  
Federica Boschi ◽  
Alessia Pascale ◽  
Annalisa Barbieri
Keyword(s):  
Neurodegenerative Diseases ◽  
Light Stimulus ◽  
The Elderly ◽  
Cell Types ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Ocular Disorders ◽  
Progressive Neurodegeneration ◽  
Underlying Mechanisms ◽  
The Brain

The possible interconnection between the eye and central nervous system (CNS) has been a topic of discussion for several years just based on fact that the eye is properly considered an extension of the brain. Both organs consist of neurons and derived from a neural tube. The visual process involves photoreceptors that receive light stimulus from the external environment and send it to retinal ganglionic cells (RGC), one of the cell types of which the retina is composed. The retina, the internal visual membrane of the eye, processes the visual stimuli in electric stimuli to transfer it to the brain, through the optic nerve. Retinal chronic progressive neurodegeneration, which may occur among the elderly, can lead to different disorders of the eye such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Mainly in the elderly population, but also among younger people, such ocular pathologies are the cause of irreversible blindness or impaired, reduced vision. Typical neurodegenerative diseases of the CSN are a group of pathologies with common characteristics and etiology not fully understood; some risk factors have been identified, but they are not enough to justify all the cases observed. Furthermore, several studies have shown that also ocular disorders present characteristics of neurodegenerative diseases and, on the other hand, CNS pathologies, i.e., Alzheimer disease (AD) and Parkinson disease (PD), which are causes of morbidity and mortality worldwide, show peculiar alterations at the ocular level. The knowledge of possible correlations could help to understand the mechanisms of onset. Moreover, the underlying mechanisms of these heterogeneous disorders are still debated. This review discusses the characteristics of the ocular illnesses, focusing on the relationship between the eye and the brain. A better comprehension could help in future new therapies, thus reducing or avoiding loss of vision and improve quality of life.

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