scholarly journals The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance and neuronal survival in mice

2019 ◽  
Author(s):  
Adi Minis ◽  
Jose Rodriguez ◽  
Avi Levin ◽  
Kai Liu ◽  
Eve-Ellen Govek ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Time Course ◽  
Binding Protein ◽  
Critical Role ◽  
Motor Dysfunction ◽  
Neurological Dysfunction ◽  
Mouse Strains ◽  
Protein Homeostasis ◽  
Term Survival ◽  
Age Related

AbstractProteasome-mediated degradation of intracellular proteins is essential for cell function and survival. The proteasome-binding protein PI31 (Proteasomal Inhibitor of 31kD) promotes 26S assembly and functions as an adapter for proteasome transport in axons. As localized protein synthesis and degradation is especially critical in neurons, we generated a conditional loss of PI31 in spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs). A cKO of PI31 in these neurons caused axon degeneration, neuronal loss and progressive spinal and cerebellar neurological dysfunction. For both MNs and PCs, markers of proteotoxic stress preceded axonal degeneration and motor dysfunction, indicating a critical role for PI31 in neuronal homeostasis. The time course of the loss of MN and PC function in developing mouse CNS suggests a key role for PI31 in human developmental neurological disorders.Statement of SignificanceThe conserved proteasome-binding protein PI31 serves as an adapter to couple proteasomes with cellular motors to mediate their transport to distal tips of neurons where protein breakdown occurs. We generated global and conditional PI31 knockout mouse strains and show that this protein is required for protein homeostasis, and that its conditional inactivation in neurons disrupts synaptic structures and long-term survival. This work establishes a critical role for PI31 and local protein degradation in the maintenance of neuronal architecture, circuitry and function. Because mutations that impair PI31 function cause neurodegenerative diseases in humans, reduced PI31 activity may contribute to age-related neurodegenerative diseases.

scholarly journals The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance, and neuronal survival in mice

2019 ◽  
Vol 116 (49) ◽  
pp. 24639-24650 ◽  
Author(s):  
Adi Minis ◽  
Jose A. Rodriguez ◽  
Avi Levin ◽  
Kai Liu ◽  
Eve-Ellen Govek ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Time Course ◽  
Cell Function ◽  
Critical Role ◽  
Neuronal Loss ◽  
Motor Dysfunction ◽  
Neurological Dysfunction ◽  
Spinal Motor Neurons ◽  
Synapse Maintenance ◽  
Cerebellar Purkinje Cells

Proteasome-mediated degradation of intracellular proteins is essential for cell function and survival. The proteasome-binding protein PI31 (Proteasomal Inhibitor of 31kD) promotes 26S assembly and functions as an adapter for proteasome transport in axons. As localized protein synthesis and degradation is especially critical in neurons, we generated a conditional loss of PI31 in spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs). A cKO of PI31 in these neurons caused axon degeneration, neuronal loss, and progressive spinal and cerebellar neurological dysfunction. For both MNs and PCs, markers of proteotoxic stress preceded axonal degeneration and motor dysfunction, indicating a critical role for PI31 in neuronal homeostasis. The time course of the loss of MN and PC function in developing mouse central nervous system suggests a key role for PI31 in human neurodegenerative diseases.

scholarly journals Corticotropin releasing factor-binding protein (CRF-BP) as a potential new therapeutic target in Alzheimer’s disease and stress disorders

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Dorien Vandael ◽  
Natalia V. Gounko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Life Stress ◽  
Binding Protein ◽  
Critical Role ◽  
Treatment Strategies ◽  
Corticotropin Releasing Factor ◽  
Stress Disorders

Abstract Alzheimer’s disease is the most common cause of dementia and one of the most complex human neurodegenerative diseases. Numerous studies have demonstrated a critical role of the environment in the pathogenesis and pathophysiology of the disease, where daily life stress plays an important role. A lot of epigenetic studies have led to the conclusion that chronic stress and stress-related disorders play an important part in the onset of neurodegenerative disorders, and an enormous amount of research yielded valuable discoveries but has so far not led to the development of effective treatment strategies for Alzheimer’s disease. Corticotropin-releasing factor (CRF) is one of the major hormones and at the same time a neuropeptide acting in stress response. Deregulation of protein levels of CRF is involved in the pathogenesis of Alzheimer’s disease, but little is known about the precise roles of CRF and its binding protein, CRF-BP, in neurodegenerative diseases. In this review, we summarize the key evidence for and against the involvement of stress-associated modulation of the CRF system in the pathogenesis of Alzheimer’s disease and discuss how recent findings could lead to new potential treatment possibilities in Alzheimer’s disease by using CRF-BP as a therapeutic target.

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

Open Biology ◽  
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.

scholarly journals SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

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.

scholarly journals Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Cells ◽  
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.

scholarly journals Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Xin Zhang ◽  
Nadine Alshakhshir ◽  
Liqin Zhao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Brain Aging ◽  
Redox Homeostasis ◽  
Critical Role ◽  
Glycolytic Flux ◽  
Glycolytic Metabolism ◽  
Age Related ◽  
Brain Resilience

Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

β2-Agonist administration increases sarcoplasmic reticulum Ca2+-ATPase activity in aged rat skeletal muscle

2005 ◽  
Vol 288 (3) ◽  
pp. E526-E533 ◽  
Author(s):  
Jonathan D. Schertzer ◽  
David R. Plant ◽  
James G. Ryall ◽  
Felice Beitzel ◽  
Nicole Stupka ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Time Course ◽  
Fiber Type ◽  
Critical Role ◽  
Maximal Activity ◽  
Contractile Properties ◽  
Kinetic Properties ◽  
Protein Levels ◽  
Age Related

Aging is associated with a slowing of skeletal muscle contractile properties, including a decreased rate of relaxation. In rats, the age-related decrease in the maximal rate of relaxation is reversed after 4-wk administration with the β2-adrenoceptor agonist (β2-agonist) fenoterol. Given the critical role of the sarcoplasmic reticulum (SR) in regulating intracellular Ca2+ transients and ultimately the time course of muscle contraction and relaxation, we tested the hypothesis that the mechanisms of action of fenoterol are mediated by alterations in SR proteins. Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) kinetic properties were assessed in muscle homogenates and enriched SR membranes isolated from the red (RG) and white (WG) portions of the gastrocnemius muscle in adult (16 mo) and aged (28 mo) F344 rats that had been administered fenoterol for 4 wk (1.4 mg/kg/day ip, in saline) or vehicle only. Aging was associated with a 29% decrease in the maximal activity ( Vmax) of SERCA in the RG but not in the WG muscles. Fenoterol treatment increased the Vmax of SERCA and SERCA1 protein levels in RG and WG. In the RG, fenoterol administration reversed an age-related selective nitration of the SERCA2a isoform. Our findings demonstrate that the mechanisms underlying age-related changes in contractile properties are fiber type dependent, whereas the effects of fenoterol administration are independent of age and fiber type.

scholarly journals ANTI-AGING PROTEIN CD9 AFFECTS AGE-RELATED HEART FAILURE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S255-S255
Author(s):  
Sriya T Jonnakuti ◽  
Mujib Ullah
Keyword(s):  
Heart Failure ◽  
Heart Function ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Heart Beat ◽  
Term Survival ◽  
Paracrine Effects ◽  
Aged Mice ◽  
Age Related ◽  
Increased Risk

Abstract The CD9 is transmembrane protein that plays a critical role in many cellular processes including aging associated cardiac pathologies. The heart function declines in the aged population. Ageing is strongly associated with many age-related conditions such as increased risk of heart failure. If aging can be prevented slowed down or even reversed, heart failure and other signs of aging could be controlled or even cured. It is unknown whether CD9 is cardioprotective. The objective of this study is to investigate whether a decline CD9 levels contributes to aging-related heart failure. Our data shows that CD9-deficient aged mice develop cardiac abnormalities and pathological cardiac hypertrophy, Cardioprotection by CD9 in old mice is followed by the downregulation of SIRT6 in the heart, and CD9 overexpressed exosomes ameliorates cardiac pathologies in treated mice and improves their long-term survival. Additionally, the serum level of CD9 decreased significantly in aged mice. CD9 overexpressed exosomes are cardioprotective and improve cardiac function in aged mice. These exosomes mediate their paracrine effects by attenuating, blood pressure, heart beat, reactive oxygen species and fibrosis. Remarkably, CD9 overexpression reversed fibrosis associated brain natriuretic peptide (BNP), Sirt6, and galectin 3 (Gal-3). These results provide a new perspective on the pathogenesis of cardiomyopathies and open new avenues for treatment of the disease.

scholarly journals The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies

2020 ◽  
Vol 52 (10) ◽  
pp. 1652-1662
Author(s):  
Myungjin Jo ◽  
Shinrye Lee ◽  
Yu-Mi Jeon ◽  
Seyeon Kim ◽  
Younghwi Kwon ◽  
...  
Keyword(s):  
Dna Binding ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Experimental Studies ◽  
Amyloid Β ◽  
Dna Binding Protein ◽  
Age Related ◽  
The Central Nervous System ◽  
Novel Therapeutic Strategies

Abstract TAR DNA-binding protein 43 (TDP-43) is a highly conserved nuclear RNA/DNA-binding protein involved in the regulation of RNA processing. The accumulation of TDP-43 aggregates in the central nervous system is a common feature of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Accumulating evidence suggests that prion-like spreading of aberrant protein aggregates composed of tau, amyloid-β, and α-synuclein is involved in the progression of neurodegenerative diseases such as AD and PD. Similar to those of prion-like proteins, pathological aggregates of TDP-43 can be transferred from cell-to-cell in a seed-dependent and self-templating manner. Here, we review clinical and experimental studies supporting the prion-like spreading of misfolded TDP-43 and discuss the molecular mechanisms underlying the propagation of these pathological aggregated proteins. The idea that misfolded TDP-43 spreads in a prion-like manner between cells may guide novel therapeutic strategies for TDP-43-associated neurodegenerative diseases.

scholarly journals Withaferin-A Treatment Alleviates TAR DNA-Binding Protein-43 Pathology and Improves Cognitive Function in a Mouse Model of FTLD

2020 ◽  
Author(s):  
Sunny Kumar ◽  
Daniel Phaneuf ◽  
Jean-Pierre Julien
Keyword(s):  
Cognitive Function ◽  
Mouse Model ◽  
Neurodegenerative Diseases ◽  
Withania Somnifera ◽  
Rna Binding ◽  
Binding Protein ◽  
Withaferin A ◽  
Age Related ◽  
The Brain ◽  
Herbal Plant

AbstractWithaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera induces autophagy, reduces TDP-43 proteinopathy, and improves cognitive function in transgenic mice expressing mutant TDP-43 modelling FTLD. TDP-43 is a nuclear DNA/RNA-binding protein with cellular functions in RNA transcription and splicing. Abnormal cytoplasmic aggregates of TDP-43 occur in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). To date, no effective treatment is available for TDP-43 proteinopathies. Here, we tested the effects of withaferin-A (WFA), an active withanolide extracted from the medicinal herbal plant Withania somnifera, in a transgenic mouse model of FTLD expressing a genomic fragment encoding mutant TDP-43G348C. WFA treatment ameliorated the cognitive performance of the TDP-43G348C mice, and it reduced NF-κB activity and neuroinflammation in the brain. WFA alleviated TDP-43 pathology while it boosted the levels of the autophagic marker LC3BII in the brain. These data suggest that WFA and perhaps other autophagy inducers should be considered as potential therapy for neurodegenerative diseases with TDP-43 pathology.

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