scholarly journals Endosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes

2020 ◽  
Vol 21 (14) ◽  
pp. 5149
Author(s):  
Ching-On Wong
Keyword(s):  
Alpha Synuclein ◽  
Amyloid Precursor Proteins ◽  
Protein Species ◽  
Metabolic Fate ◽  
Cellular Toxicity ◽  
Precursor Proteins ◽  
Associated Proteins ◽  
Lysosomal System ◽  
The Brain

Most common neurodegenerative diseases (NDs) are characterized by deposition of protein aggregates that are resulted from misfolding, dysregulated trafficking, and compromised proteolytic degradation. These proteins exert cellular toxicity to a broad range of brain cells and are found in both neurons and glia. Extracellular monomeric and oligomeric ND-associated proteins are taken up by astrocytes, the most abundant glial cell in the brain. Internalization, intracellular trafficking, processing, and disposal of these proteins are executed by the endosomal-lysosomal system of astrocytes. Endosomal-lysosomal organelles thus mediate the cellular impact and metabolic fate of these toxic protein species. Given the indispensable role of astrocytes in brain metabolic homeostasis, the endosomal-lysosomal processing of these proteins plays a fundamental role in altering the trajectory of neurodegeneration. This review aims at summarizing the mounting evidence that has established the essential role of astrocytic endosomal-lysosomal organelles in the processing of amyloid precursor proteins, Apolipoprotein E (ApoE), tau, alpha synuclein, and huntingtin, which are associated with NDs such as Alzheimer’s, Parkinson’s, and Huntington diseases.

scholarly journals Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

2022 ◽  
Author(s):  
Min Hyung Seo ◽  
Sujung Yeo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Cell Loss ◽  
Alpha Synuclein ◽  
Mice Model ◽  
Dopaminergic Cell ◽  
The Brain

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

The Two Faces of Exosomes in Parkinson’s Disease: From Pathology to Therapy

2021 ◽  
pp. 107385842199000
Author(s):  
Maria Izco ◽  
Estefania Carlos ◽  
Lydia Alvarez-Erviti
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Drug Delivery System ◽  
Glial Cells ◽  
Delivery System ◽  
Alpha Synuclein ◽  
Macromolecular Drugs ◽  
The Brain

Accumulating evidence suggests that exosomes play a key role in Parkinson’s disease (PD). Exosomes may contribute to the PD progression facilitating the spread of pathological alpha-synuclein or activating immune cells. Glial cells also release exosomes, and transmission of exosomes derived from activated glial cells containing inflammatory mediators may contribute to the propagation of the neuroinflammatory response. Glia-to-neuron transmission of exosomes containing alpha-synuclein may contribute to alpha-synuclein propagation and neurodegeneration. Additionally, miRNAs can be transmitted among cells via exosomes inducing changes in the genetic program of the target cell contributing to PD progression. Exosomes also represent a promising drug delivery system. The brain is a difficult target for drugs of all classes because the blood-brain barrier excludes most macromolecular drugs. One of the major challenges is the development of vehicles for robust delivery to the brain. Targeted exosomes may have the potential for delivering therapeutic agents, including proteins and gene therapy molecules, into the brain. This review summarizes recent advances in the role of exosomes in PD pathology progression and their potential use as drug delivery system for PD treatment, the two faces of the exosomes in PD.

scholarly journals Map1b Is Required for Axon Guidance and Is Involved in the Development of the Central and Peripheral Nervous System

2000 ◽  
Vol 151 (6) ◽  
pp. 1169-1178 ◽  
Author(s):  
Arabella Meixner ◽  
Silke Haverkamp ◽  
Heinz Wässle ◽  
Susanne Führer ◽  
Johann Thalhammer ◽  
...  
Keyword(s):  
Nervous System ◽  
Nerve Conduction Velocity ◽  
Developmental Defect ◽  
Myelinated Fiber ◽  
Microtubule Associated Proteins ◽  
Associated Proteins ◽  
And Function ◽  
The Brain ◽  
Deficient Mice

Microtubule-associated proteins such as MAP1B have long been suspected to play an important role in neuronal differentiation, but proof has been lacking. Previous MAP1B gene targeting studies yielded contradictory and inconclusive results and did not reveal MAP1B function. In contrast to two earlier efforts, we now describe generation of a complete MAP1B null allele. Mice heterozygous for this MAP1B deletion were not affected. Homozygous mutants were viable but displayed a striking developmental defect in the brain, the selective absence of the corpus callosum, and the concomitant formation of myelinated fiber bundles consisting of misguided cortical axons. In addition, peripheral nerves of MAP1B-deficient mice had a reduced number of large myelinated axons. The myelin sheaths of the remaining axons were of reduced thickness, resulting in a decrease of nerve conduction velocity in the adult sciatic nerve. On the other hand, the anticipated involvement of MAP1B in retinal development and γ-aminobutyric acid C receptor clustering was not substantiated. Our results demonstrate an essential role of MAP1B in development and function of the nervous system and resolve a previous controversy over its importance.

scholarly journals Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

2020 ◽  
Vol 21 (14) ◽  
pp. 5030
Author(s):  
Elena Vacchi ◽  
Alain Kaelin-Lang ◽  
Giorgia Melli
Keyword(s):  
Neurodegenerative Diseases ◽  
Alpha Synuclein ◽  
Anatomical Connectivity ◽  
Peripheral Tissues ◽  
Parkinson’S Diseases ◽  
Relevant Role ◽  
The Brain ◽  
Dying Back

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

P2-328: Role of amyloid precursor proteins and beta-amyloid-induced synaptic dysfunction

2010 ◽  
Vol 6 ◽  
pp. S409-S409
Author(s):  
Sheue-Houy Tyan ◽  
Brea Midthune ◽  
Simone Eggert ◽  
Dara L. Dickstein ◽  
Edward H. Koo
Keyword(s):  
Beta Amyloid ◽  
Synaptic Dysfunction ◽  
Amyloid Precursor Proteins ◽  
Precursor Proteins

scholarly journals Influence of Metal Ions on Microtubules as a Possible Mechanism of Pathogenesis of Alzheimer′s Disease

2018 ◽  
Vol 1 (3) ◽  
pp. e00050
Author(s):  
P.N. Shevtsov ◽  
E.F. Shevtsova ◽  
S.O. Bachurin
Keyword(s):  
Metal Ions ◽  
Inferior Olive ◽  
Postmortem Brain ◽  
Control Group ◽  
Destructive Effect ◽  
Aluminum Ions ◽  
Associated Proteins ◽  
The Brain

The article provides an overview of our own results of comparative study of influence of ions of iron, zinc and aluminium on the structure of microtubules from tubulin and microtubules associated proteins of rat brain with data on the structure of microtubules from tubulin and microtubules associated proteins from the brain of patients with Alzheimer′s disease (AD). A significant decrease in the amount of soluble tubulin was found in the postmortem brain of AD patients in comparison with the control group in the hippocampus, frontal cortex and substantia nigra, but not in the inferior olive. In vitro polymerization of tubulin and microtubules associated proteins from the brain of AD patients and electron micrographs of microtubules were obtained. The assembly of microtubules from brains of AD patients is disrupted, resulting in defective structures. On the other hand, the study of the influence of Al3+, Fe3+, Zn2+ on the microtubules from rat brains tubulin and microtubules associated proteins assembly and structure has shown that all studied metals are able to reduce the amount of microtubules and induce the assembly of anomal structures. According to the degree of the destructive effect on the microtubules and, accordingly, the possible significance in the pathogenesis of Alzheimer disease, metal ions can be arranged in the following sequence Al3+ > Zn2+ > Fe3+. Moreover, phosphorylation of tubulin and microtubules associated proteins in the presence of aluminum ions to the greatest extent reflects the phosphorylation of these proteins at AD. Comparison of data on the structure of microtubules after their assembly from brains of AD patients tubulin and microtubules associated proteins from brains of AD patients, and from the brain of rats, but in the presence of metal ions, confirm the conclusion about the possible role of the metals in the AD etiopathogenesis.

scholarly journals Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora

2021 ◽  
Author(s):  
Pasquale Pellegrini ◽  
Arnau Hervera ◽  
Olga Varea ◽  
M. Kathryn Brewer ◽  
Iliana López-Soldado ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Tissue ◽  
Protective Mechanism ◽  
Lafora Disease ◽  
Childhood Onset ◽  
Neurological Phenotype ◽  
Associated Proteins ◽  
The Brain ◽  
Increased Susceptibility

Abstract Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates—the so-called Lafora Bodies (LBs)—in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.

scholarly journals Tau in Health and Neurodegenerative Diseases

2021 ◽  
Author(s):  
Dandan Chu ◽  
Fei Liu
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Dynamic Properties ◽  
Corticobasal Degeneration ◽  
Microtubule Associated Proteins ◽  
Associated Proteins ◽  
Argyrophilic Grain ◽  
The Brain ◽  
Filamentous Inclusions

Tau, one of the major microtubule-associated proteins, modulates the dynamic properties of microtubules in the mammalian nervous system. Tau is abundantly expressed in the brain, particularly in the hippocampus. Insoluble and filamentous inclusions of tau in neurons or glia are discovered in neurodegenerative diseases termed ‘tauopathies’, including Alzheimer’s disease (AD), argyrophilic grain disease (AGD), corticobasal degeneration (CBD), frontotemporal dementia (FTD), Pick’s disease (PiD) and progressive supranuclear palsy (PSP). Accumulation of intracellular neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau, is directly correlated with the degree of Alzheimer\'s dementia. This chapter reviews the role of tau protein in physiological conditions and the pathological changes of tau related to neurodegenerative diseases. The applications of tau as a therapeutic target are also discussed.

scholarly journals Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice

2020 ◽  
Vol 29 (14) ◽  
pp. 2300-2312 ◽  
Author(s):  
Ping-Yue Pan ◽  
Patricia Sheehan ◽  
Qian Wang ◽  
Xinyu Zhu ◽  
Yuanxi Zhang ◽  
...  
Keyword(s):  
Alpha Synuclein ◽  
Midbrain Neurons ◽  
Phosphoinositide Phosphatase ◽  
Phospholipid Signaling ◽  
Age Dependent ◽  
Terminal Degeneration ◽  
Trafficking Defects ◽  
The Brain ◽  
Dopaminergic Terminal

Abstract Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5′-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/−), which is associated with an impaired 5′-phosphatase activity, also leads to Parkinson’s disease (PD)-like pathologies in mice. We report that male Synj1+/− mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1+/− mice contain elevated 5′-phosphatase substrate, PI(4,5)P2, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P2 in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1+/− midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.

scholarly journals HDL Proteome and Alzheimer’s Disease: Evidence of a Link

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1224
Author(s):  
Judit Marsillach ◽  
Maria Pia Adorni ◽  
Francesca Zimetti ◽  
Bianca Papotti ◽  
Giovanni Zuliani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Density Lipoprotein ◽  
Paraoxonase 1 ◽  
Beneficial Effects ◽  
Current State ◽  
Associated Proteins ◽  
Main Determinants ◽  
The Brain

Several lines of epidemiological evidence link increased levels of high-density lipoprotein-cholesterol (HDL-C) with lower risk of Alzheimer’s disease (AD). This observed relationship might reflect the beneficial effects of HDL on the cardiovascular system, likely due to the implication of vascular dysregulation in AD development. The atheroprotective properties of this lipoprotein are mostly due to its proteome. In particular, apolipoprotein (Apo) A-I, E, and J and the antioxidant accessory protein paraoxonase 1 (PON1), are the main determinants of the biological function of HDL. Intriguingly, these HDL constituent proteins are also present in the brain, either from in situ expression, or derived from the periphery. Growing preclinical evidence suggests that these HDL proteins may prevent the aberrant changes in the brain that characterize AD pathogenesis. In the present review, we summarize and critically examine the current state of knowledge on the role of these atheroprotective HDL-associated proteins in AD pathogenesis and physiopathology.

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