The Michael J. Fox Foundation for Parkinson’s Research Strategy to Advance Therapeutic Development of PINK1 and Parkin

The role of mitochondria in Parkinson’s disease (PD) has been investigated since the 1980s and is gaining attention with recent advances in PD genetics research. Mutations in PRKN and PTEN-Induced Putative Kinase 1 (PINK1) are well-established causes of autosomal recessive early-onset PD. Genetic and biochemical studies have revealed that PINK1 and Parkin proteins function together in the same biological pathway to govern mitochondrial quality control. These proteins have also been implicated in the regulation of innate and adaptive immunity and other mitochondrial functions. Additionally, structural studies on Parkin have delineated an activation mechanism and have identified druggable regions that are currently being explored by academic and industry groups. To de-risk therapeutic development for these genetic targets, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has deployed a strategic funding and enabling framework that brings together the research community to discuss important breakthroughs and challenges in research on PINK1-Parkin biology, supports collaborative initiatives to further our understanding within this field and develops high-quality research tools and assays that are widely available to all researchers. The Foundation’s efforts are leading to significant advances in understanding of the underlying biology of these genes, proteins and pathways and in the development of Parkinson’s therapies.

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Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

International Journal of Molecular Sciences ◽

10.3390/ijms23010552 ◽

2022 ◽

Vol 23 (1) ◽

pp. 552

Author(s):

Jaya Bagaria ◽

Eva Bagyinszky ◽

Seong Soo A. An

Keyword(s):

Neurodegenerative Diseases ◽

Autosomal Recessive ◽

Genetic Mutations ◽

Compound Heterozygous ◽

French Canadians ◽

Pes Cavus ◽

Spastic Ataxia ◽

Mitochondrial Functions ◽

Limb Deformities

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

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“Wi, se kretyènn mwen ye” (Yes I am Christian)

Fieldwork in Religion ◽

10.1558/firn.v5i2.180 ◽

2011 ◽

Vol 5 (2) ◽

pp. 180-192 ◽

Cited By ~ 1

Author(s):

Nadège Mézié

Keyword(s):

Field Study ◽

Religious Identity ◽

Research Strategy ◽

Beliefs And Practices ◽

Christian Woman

During a field study of a year and a half in the Haitian mountains, I was forced to re-evaluate my research strategy, and consequently the object of my study, after a setback that denied me access to the American evangelical mission, which I had hoped to study from within. This failure to integrate as a non-Protestant researcher, led me to adopt a methodological falsehood to allow me to penetrate the Haitian evangelical mission. The researcher who chooses methodological falsehood has to fashion a passing and superficial redefinition of her appearance, beliefs and practices, and live her new religious identity according to the prevalent beliefs and norms. This paper will focus on the fieldworker’s daily performance in her role of “Christian woman,” and the strategies put in place to respond to the prescriptive criteria of the role being played.

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Papillon-Lefevre Syndrome: Challenge for Periodontal Management

Journal of Nepalese Society of Periodontology and Oral Implantology ◽

10.3126/jnspoi.v3i2.30891 ◽

2019 ◽

Vol 3 (2) ◽

pp. 84-86

Author(s):

Krishna Prasad Lamichhane ◽

Shaili Pradhan ◽

Ranjita Shreshta Gorkhali ◽

Pramod Kumar Koirala

Keyword(s):

Significant Role ◽

Autosomal Recessive ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Genetic Mutations ◽

Rare Autosomal Recessive Disorder ◽

Diagnosis And Management ◽

Periodontal Destruction ◽

Palmoplantar Keratosis

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder associated with rapidly progressing periodontitis leading to premature loss of deciduous and permanent dentition and diffuse palmoplantar keratosis. Immunologic alterations, genetic mutations, and role of bacteria are some aetiologic factors. Patients present with early periodontal destruction, so periodontists play a significant role in diagnosis and management. This paper reports a case of Papillon- Lefevre syndrome with its clinical manifestations and challenges for periodontal management which was diagnosed in dental department.

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STRUCTURAL COMPONENTS OF THE PRIVATE MEDICAL SECTOR ACTIVATION MECHANISM

Economical ◽

10.31474/1680-0044-2019-2(21)-170-177 ◽

2019 ◽

Vol 2 (2(21)) ◽

pp. 170-177

Author(s):

Anzhela Bairak ◽

Keyword(s):

Health Care ◽

Health Care System ◽

Activation Mechanism ◽

Practical Significance ◽

Structural Components ◽

Medical Sector ◽

Analysis And Synthesis ◽

Private Medicine ◽

Care System

The article examines the problems of private medicine in the health care system of the country. The aim of the article is to determine the structural components of the mechanism of activation of the private medical sector as a reserve for the provision of quality and affordable medical services and a driver for the development of the medical industry. The descriptive-analytical method, methods of analysis and synthesis, comparison, statistical, analysis and scientific generalization were used in the paper. The study substantiates the strengthening of the role of the private medical sector in the health care management system. The key problems of the domestic private medical sector and the restraining factors of its development are identified. It is concluded that it is necessary to develop a mechanism to promote the development of private medicine through a policy of active change in the health care system. The directions of activation of the private medical sector as a target reference point in the process of determining the structural elements of the organizational and economic mechanism are outlined. The structural detail of the mechanism of activation of the private medical sector for optimization of the health care system is offered. The practical significance of the obtained results is that the results of the research presented in the article are a practical basis for the development and improvement of mechanisms of public administration in the field of health care.

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Overview on the Different Patterns of Tumor Vascularization

Cells ◽

10.3390/cells10030639 ◽

2021 ◽

Vol 10 (3) ◽

pp. 639

Author(s):

Domenico Ribatti ◽

Francesco Pezzella

Keyword(s):

Vasculogenic Mimicry ◽

Endothelial Cell Proliferation ◽

Published Data ◽

Alternative Mechanism ◽

Tumor Vascularization ◽

Angiogenic Therapy ◽

Physiological Processes ◽

Inhibition Of Angiogenesis ◽

Therapeutic Development

Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.

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Role of Mitochondria in Viral Infections

Life ◽

10.3390/life11030232 ◽

2021 ◽

Vol 11 (3) ◽

pp. 232

Author(s):

Srikanth Elesela ◽

Nicholas W. Lukacs

Keyword(s):

Viral Infections ◽

Mitochondrial Dynamics ◽

The Body ◽

Viral Diseases ◽

Multiple Organs ◽

Innate Immune Signaling ◽

Mitochondrial Functions ◽

Host Virus Interactions ◽

Virus Interactions

Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases.

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PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

International Journal of Molecular Sciences ◽

10.3390/ijms22105112 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5112

Author(s):

Lotte van Beek ◽

Éilís McClay ◽

Saleha Patel ◽

Marianne Schimpl ◽

Laura Spagnolo ◽

...

Keyword(s):

Dna Damage ◽

Dna Binding ◽

Parp Inhibitors ◽

Covalent Modification ◽

Activation Mechanism ◽

Cancer Therapies ◽

Damage Repair ◽

Complementary Role ◽

Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

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Fit Perception and Engagement: The Mediating Role of Work Meaningfulness

Vision The Journal of Business Perspective ◽

10.1177/0972262921999866 ◽

2021 ◽

pp. 097226292199986

Author(s):

Robinson James

Keyword(s):

Employee Engagement ◽

Structural Equation ◽

Strong Predictor ◽

Organizational Outcomes ◽

Research Strategy ◽

Partial Least Square ◽

Least Square ◽

Future Research ◽

Work Meaningfulness

Research on engagement has gained considerable attention in recent years as it is a strong predictor of a range of positive individual and organizational outcomes. There is a question of why the level of the engagement is different from employee to employee in an organization, though they are provided with the same resources. This study aims to investigate the influence of fit perception on engagement and the role of the employee’s psychological condition (work meaningfulness) on this relationship. This study mainly employed a survey research strategy, and data were primarily garnered from a questionnaire. This study was conducted among 145 respondents from the public sector organizations in Sri Lanka. Partial least-square structural equation modelling was employed to analyse the generated data. In this study, the researcher has conceptualized fit perception as a higher order construct comprising Person Job fit and Person Organization fit. The study revealed that fit perception positively influences employee engagement, and this relationship is mediated by work meaningfulness. This study contributes to the literature by deepening the understanding of the fit perception and engagement relationship by introducing work meaningfulness as a mediator variable. By highlighting how engagement is influenced by fit perception and work meaningfulness, this study facilitates practitioners to build and maintain an engaged workforce. Further contributions of this study, the avenue for future research, and study limitations are presented in detail at the end of this article.

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Roles of ncRNAs as ceRNAs in Gastric Cancer

Genes ◽

10.3390/genes12071036 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1036

Author(s):

Junhong Ye ◽

Jifu Li ◽

Ping Zhao

Keyword(s):

Gastric Cancer ◽

Research Strategy ◽

Circular Rnas ◽

Messenger Rnas ◽

Cerna Network ◽

Degree Of Malignancy ◽

High Degree ◽

Competitive Endogenous Rna ◽

Made In

Although ignored in the past, with the recent deepening of research, significant progress has been made in the field of non-coding RNAs (ncRNAs). Accumulating evidence has revealed that microRNA (miRNA) response elements regulate RNA. Long ncRNAs, circular RNAs, pseudogenes, miRNAs, and messenger RNAs (mRNAs) form a competitive endogenous RNA (ceRNA) network that plays an essential role in cancer and cardiovascular, neurodegenerative, and autoimmune diseases. Gastric cancer (GC) is one of the most common cancers, with a high degree of malignancy. Considerable progress has been made in understanding the molecular mechanism and treatment of GC, but GC’s mortality rate is still high. Studies have shown a complex ceRNA crosstalk mechanism in GC. lncRNAs, circRNAs, and pseudogenes can interact with miRNAs to affect mRNA transcription. The study of the involvement of ceRNA in GC could improve our understanding of GC and lead to the identification of potential effective therapeutic targets. The research strategy for ceRNA is mainly to screen the different miRNAs, lncRNAs, circRNAs, pseudogenes, and mRNAs in each sample through microarray or sequencing technology, predict the ceRNA regulatory network, and, finally, conduct functional research on ceRNA. In this review, we briefly discuss the proposal and development of the ceRNA hypothesis and the biological function and principle of ceRNAs in GC, and briefly introduce the role of ncRNAs in the GC’s ceRNA network.

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TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00711-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xueer Wang ◽

Honghai Zhang ◽

Zhugui Shao ◽

Wanxin Zhuang ◽

Chao Sui ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Fungal Pathogen ◽

Essential Role ◽

Molecular Mechanisms ◽

Systemic Infection ◽

Lectin Receptors ◽

Innate And Adaptive Immunity ◽

Cytokines And Chemokines

AbstractSpleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31−/− mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

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