Sirtuins are NAD‐dependent protein deacetylases known to have protective effects against age‐related diseases such as cancer, diabetes, cardiovascular and neurodegenerative diseases. In mammals, ...there are seven sirtuins (SIRT1‐7), which display diversity in subcellular localization and function. While SIRT1 has been extensively investigated due to its initial connection with lifespan extension and involvement in calorie restriction, important biological and therapeutic roles of other sirtuins have only recently been recognized. Here, we review the potential roles and effects of SIRT1 and SIRT2 in neurodegenerative diseases. We discuss different functions and targets of SIRT1 and SIRT2 in a variety of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's Disease (HD). We also cover the role of SIRT1 in neuronal differentiation due to the possible implications in neurodegenerative conditions, and conclude with an outlook on the potential therapeutic value of SIRT1 and SIRT2 in these disorders.
Sirtuins (SIRTs) are NAD‐dependent protein deacetylases, which have been implicated in age‐related diseases. This review discusses recent findings on the roles of SIRT1 and SIRT2 in neurodegenerative diseases and in potential therapeutic approaches.
Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these ...disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system.
Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene ...encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Misfolding and aggregation of alpha‐synuclein (α‐synuclein) with concomitant cytotoxicity is a hallmark of Lewy body related disorders such as Parkinson’s disease, dementia with Lewy bodies, and ...multiple system atrophy. Although it plays a pivotal role in pathogenesis and disease progression, the function of α‐synuclein and the molecular mechanisms underlying α‐synuclein‐induced neurotoxicity in these diseases are still elusive. Many in vitro and in vivo experimental models mimicking α‐synuclein pathology such as oligomerization, toxicity and more recently neuronal propagation have been generated over the years. In particular, cellular models have been crucial for our comprehension of the pathogenic process of the disease and are beneficial for screening of molecules capable of modulating α‐synuclein toxicity. Here, we review α‐synuclein based cell culture models that reproduce some features of the neuronal populations affected in patients, from basic unicellular organisms to mammalian cell lines and primary neurons, to the cutting edge models of patient‐specific cell lines. These reprogrammed cells known as induced pluripotent stem cells (iPSCs) have garnered attention because they closely reproduce the characteristics of neurons found in patients and provide a valuable tool for mechanistic studies. We also discuss how different cell models may constitute powerful tools for high‐throughput screening of molecules capable of modulating α‐synuclein toxicity and prevention of its propagation.
This article is part of the Special Issue “Synuclein”.
The ability to model cellular characteristics of synucleinopathies in a petri dish can offer myriad opportunities for studying pathogenic mechanisms and aid the development and validation of future pharmacological interventions. Here, we review available cellular models to study α‐synuclein toxicity from basic unicellular organisms to mammalian cell linesand primary neurons, to more recent cellular systems such as human induced pluripotent stem cells. We describe the strategies employed to monitor and measure α‐synuclein–induced dysfunction and discuss how these models constitute powerful tools for high‐throughput screening of molecules capable of modulating α‐synuclein toxicity and preventing propagation.
This article is part of the Special Issue “Synuclein”.
The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory ...cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of LRRK2 in cell signalling Harvey, Kirsten; Outeiro, Tiago F
Biochemical Society transactions,
02/2019, Letnik:
47, Številka:
1
Journal Article
Recenzirano
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Parkinson's disease (PD) is a common late-onset neurodegenerative disorder known primarily for its motor features. Mutations and risk variants in
cause familial and idiopathic forms of PD. Mutations ...segregating with disease are found in the LRRK2 GTPase and kinase domains, affecting catalytic activity and protein-protein interactions. This likely results in an overall gain of LRRK2 cell signalling function contributing to PD pathogenesis. This concept supports the development of LRRK2 kinase inhibitors as disease-modifying treatments, at least for a subset of patients. However, the function of LRRK2 as a cell signalling protein with two catalytic and several protein-protein interaction domains is highly complex. For example, LRRK2 plays important roles in several inflammatory diseases, raising the possibility that it may mediate immune responses in PD. Consistently, LRRK2-mediated cell signalling was not only shown to be important for neuronal function, including neuronal development and homeostasis, but also for peripheral and central immune responses. The catalytic activity of LRRK2 is regulated by autophosphorylation, protein monomer/dimer cycling, and upstream kinases and GTPases, affecting its subcellular localisation and downstream signalling. Part of LRRK2-mediated signalling is likely facilitated by Rab protein phosphorylation, affecting primarily membrane trafficking, including vesicle release at the trans-Golgi network. However, LRRK2 also displays intrinsic GTPase activity and functions as a signalling scaffold. As an example, LRRK2 was suggested to be part of the NRON complex and β-catenin destruction complex, inhibiting NFAT and canonical Wnt signalling, respectively. In summary, continuous research into LRRK2 signalling function contributes to novel diagnostic and therapeutic concepts in PD.
Movement disorders can be primarily divided into hypokinetic and hyperkinetic. Most of the hypokinetic syndromes are associated with the neurodegenerative disorder Parkinson's disease (PD). By ...contrast, hyperkinetic syndromes encompass a broader array of diseases, including dystonia, essential tremor, or Huntington's disease. The discovery of effective therapies for these disorders has been challenging and has also involved the development and characterization of accurate animal models for the screening of new drugs. Zebrafish constitutes an alternative vertebrate model for the study of movement disorders. The neuronal circuitries involved in movement in zebrafish are well characterized, and most of the associated molecular mechanisms are highly conserved. Particularly, zebrafish models of PD have contributed to a better understanding of the role of several genes implicated in the disease. Furthermore, zebrafish is a vertebrate model particularly suited for large-scale drug screenings. The relatively small size of zebrafish, optical transparency, and lifecycle, are key characteristics that facilitate the study of multiple compounds at the same time. Several transgenic, knockdown, and mutant zebrafish lines have been generated and characterized. Therefore, it is central to critically analyze these zebrafish lines and understand their suitability as models of movement disorders. Here, we revise the pathogenic mechanisms, phenotypes, and responsiveness to pharmacotherapies of zebrafish lines of the most common movement disorders. A systematic review of the literature was conducted by including all studies reporting the characterization of zebrafish models of the movement disorders selected from five bibliographic databases. A total of 63 studies were analyzed, and the most relevant data within the scope of this review were gathered. The majority (62%) of the studies were focused in the characterization of zebrafish models of PD. Overall, the zebrafish models included display conserved biochemical and neurobehavioral features of the phenomenology in humans. Nevertheless, in light of what is known for all animal models available, the use of zebrafish as a model for drug discovery requires further optimization. Future technological developments alongside with a deeper understanding of the molecular bases of these disorders should enable the development of novel zebrafish lines that can prove useful for drug discovery for movement disorders.
Tau deletion promotes brain insulin resistance Marciniak, Elodie; Leboucher, Antoine; Caron, Emilie ...
The Journal of experimental medicine,
08/2017, Letnik:
214, Številka:
8
Journal Article
Recenzirano
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The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and ...fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients.
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