scholarly journals Atypical Pantothenate Kinase-Associated Neurodegeneration with Variable Phenotypes in an Egyptian Family

2021 ◽  
Author(s):  
Ali Shalash ◽  
Thomas Rösler ◽  
Ibrahim Abdelrahman ◽  
Hatem Abulmakarem ◽  
Stefanie Müller ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Disease Progression ◽  
Exome Sequencing ◽  
Present Report ◽  
Clinical Manifestations ◽  
Slow Disease Progression ◽  
Pantothenate Kinase ◽  
Causative Variant ◽  
The Brain

Abstract Pantothenate kinase-associated neurodegeneration (PKAN) is a rare hereditary neurodegenerative disease characterized by an accumulation of iron within the brain. In the present report, we describe a family with 4 affected siblings presenting with variable clinical manifestations, e.g., parkinsonian features, dystonia and slow disease progression over 5 years. Exome sequencing revealed a causative variant in the pantothenate kinase 2 gene (PANK2). Variant NM_024960.6:c.710C > T was homozygous in all affected subjects. Our report describes the first genetically confirmed cases of PKAN in the Egyptian population. Studying genetics of neurodegenerative diseases in different ethnicities is very important for determining clinical phenotypes and understanding pathomechanisms of these diseases.

scholarly journals Transcellular spreading of huntingtin aggregates in the Drosophila brain

2015 ◽  
Vol 112 (39) ◽  
pp. E5427-E5433 ◽  
Author(s):  
Daniel T. Babcock ◽  
Barry Ganetzky
Keyword(s):  
Fusion Protein ◽  
Neurodegenerative Diseases ◽  
Disease Progression ◽  
Protein Aggregates ◽  
Misfolded Proteins ◽  
Drosophila Brain ◽  
Active Release ◽  
Fluorescent Tag ◽  
The Brain ◽  
Expanded Form

A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington’s disease. Upon expression of this construct in a defined subset of neurons, we demonstrate that protein aggregates accumulate at synaptic terminals and progressively spread throughout the brain. These aggregates are internalized and accumulate within other neurons. We show that Htt aggregates cause non–cell-autonomous pathology, including loss of vulnerable neurons that can be prevented by inhibiting endocytosis in these neurons. Finally we show that the release of aggregates requires N-ethylmalemide–sensitive fusion protein 1, demonstrating that active release and uptake of Htt aggregates are important elements of spreading and disease progression.

scholarly journals Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

2021 ◽  
Vol 14 ◽  
Author(s):  
Raja Elizabeth Estes ◽  
Bernice Lin ◽  
Arnav Khera ◽  
Marie Ynez Davis
Keyword(s):  
Lipid Metabolism ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Disease Progression ◽  
Protein Aggregates ◽  
Disease Etiology ◽  
Abnormal Protein ◽  
System A ◽  
Novel Therapeutic

Many neurodegenerative diseases are characterized by abnormal protein aggregates, including the two most common neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). In the global search to prevent and treat diseases, most research has been focused on the early stages of the diseases, including how these pathogenic protein aggregates are initially formed. We argue, however, that an equally important aspect of disease etiology is the characteristic spread of protein aggregates throughout the nervous system, a key process in disease progression. Growing evidence suggests that both alterations in lipid metabolism and dysregulation of extracellular vesicles (EVs) accelerate the spread of protein aggregation and progression of neurodegeneration, both in neurons and potentially in surrounding glia. We will review how these two pathways are intertwined and accelerate the progression of AD and PD. Understanding how lipid metabolism, EV biogenesis, and EV uptake regulate the spread of pathogenic protein aggregation could reveal novel therapeutic targets to slow or halt neurodegenerative disease progression.

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 Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

2022 ◽  
Vol 23 (2) ◽  
pp. 629
Author(s):  
Xiangli Zhao ◽  
Sadaf Hasan ◽  
Benjamin Liou ◽  
Yi Lin ◽  
Ying Sun ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Brain Tissue ◽  
Clinical Settings ◽  
Progressive Degeneration ◽  
Disease Modifying Therapies ◽  
Β Amyloid ◽  
And Function ◽  
The Brain ◽  
Deficient Mice

Neurodegenerative diseases are debilitating impairments that affect millions of people worldwide and are characterized by progressive degeneration of structure and function of the central or peripheral nervous system. Effective biomarkers for neurodegenerative diseases can be used to improve the diagnostic workup in the clinic as well as facilitate the development of effective disease-modifying therapies. Progranulin (PGRN) has been reported to be involved in various neurodegenerative disorders. Hence, in the current study we systematically compared the inflammation and accumulation of typical neurodegenerative disease markers in the brain tissue between PGRN knockout (PGRN KO) and wildtype (WT) mice. We found that PGRN deficiency led to significant neuron loss as well as activation of microglia and astrocytes in aged mice. Several characteristic neurodegenerative markers, including α-synuclein, TAR DNA-binding protein 43 (TDP-43), Tau, and β-amyloid, were all accumulated in the brain of PGRN-deficient mice as compared to WT mice. Moreover, higher aggregation of lipofuscin was observed in the brain tissue of PGRN-deficient mice compared with WT mice. In addition, the autophagy was also defective in the brain of PGRN-deficient mice, indicated by the abnormal expression level of autophagy marker LC3-II. Collectively, comprehensive assays support the idea that PGRN plays an important role during the development of neurodegenerative disease, indicating that PGRN might be a useful biomarker for neurodegenerative diseases in clinical settings.

scholarly journals CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS

2008 ◽  
Vol 105 (40) ◽  
pp. 15558-15563 ◽  
Author(s):  
David R. Beers ◽  
Jenny S. Henkel ◽  
Weihua Zhao ◽  
Jinghong Wang ◽  
Stanley H. Appel
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Neurodegenerative Diseases ◽  
Disease Progression ◽  
Cd4 T Cells ◽  
Trophic Factors ◽  
Pathological Feature ◽  
Mrna Levels ◽  
Slow Disease Progression ◽  
Novel Target

Neuroinflammation, marked by gliosis and infiltrating T cells, is a prominent pathological feature in diverse models of dominantly inherited neurodegenerative diseases. Recent evidence derived from transgenic mice ubiquitously overexpressing mutant Cu2+/Zn2+ superoxide dismutase (mSOD1), a chronic neurodegenerative model of inherited amyotrophic lateral sclerosis (ALS), indicates that glia with either a lack of or reduction in mSOD1 expression enhance motoneuron protection and slow disease progression. However, the contribution of T cells that are present at sites of motoneuron injury in mSOD1 transgenic mice is not known. Here we show that when mSOD1 mice were bred with mice lacking functional T cells or CD4+ T cells, motoneuron disease was accelerated, accompanied by unexpected attenuated morphological markers of gliosis, increased mRNA levels for proinflammatory cytokines and NOX2, and decreased levels of trophic factors and glial glutamate transporters. Bone marrow transplants reconstituted mice with T cells, prolonged survival, suppressed cytotoxicity, and restored glial activation. These results demonstrate for the first time in a model of chronic neurodegeneration that morphological activation of microglia and astroglia does not predict glial function, and that the presence of CD4+ T cells provides supportive neuroprotection by modulating the trophic/cytotoxic balance of glia. These glial/T-cell interactions establish a novel target for therapeutic intervention in ALS and possibly other neurodegenerative diseases.

scholarly journals Neuronal intranuclear inclusion disease with mental abnormality: a case report

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaosa Chi ◽  
Man Li ◽  
Ting Huang ◽  
Kangyong Tong ◽  
Hongyi Xing ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Clinical Work ◽  
Intranuclear Inclusions ◽  
Intranuclear Inclusion ◽  
Corticomedullary Junction ◽  
Normal White Blood Cell ◽  
Neuronal Intranuclear Inclusion ◽  
The Brain

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a chronic progressive neurodegenerative disease that is characterized by the discovery of eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous systems and visceral organs. In this paper, we report a case of an adult-onset neuronal intranuclear inclusion disease presenting with mental abnormality in China. Case presentation A 62-year-old woman presented with mental abnormality and forgetfulness for 3 months before she was admitted to our hospital. There were prodromal symptoms of fever before she had the mental disorder. Encephalitis was first suspected, and the patient underwent lumbar puncture and brain magnetic resonance imaging (MRI). A cerebrospinal fluid (CSF) examination indicated normal pressure, a normal white blood cell count, and slightly elevated protein and glucose levels. Coxsackie B virus, enterovirus, and cytomegalovirus tests showed normal results. Bacterial culture and Cryptococcus neoformans test results were negative. The contrast-enhanced MRI of the brain was normal. The brain diffusion-weighted imaging (DWI) showed a symmetrically distributed strip-shaped hyperintensity signal of the corticomedullary junction in the bilateral frontal, parietal, and temporal lobes. We considered the diagnosis of the NIID, and therefore, skin biopsy was performed. The electron microscopy revealed that intranuclear inclusions in the nucleus of fibrocytes existed and were composed of filaments. Conclusions NIID is a rare neurodegenerative disease with diverse clinical manifestations. In clinical work, when a patient presents with abnormal mental behavior and exhibits hyperintensity signals on DWI images of the corticomedullary junction, it is crucial to consider the diagnosis of NIID.

Human neuronal cells: epigenetic aspects

2013 ◽  
Vol 4 (4) ◽  
pp. 319-333 ◽  
Author(s):  
Jessica Kukucka ◽  
Tessa Wyllie ◽  
Justin Read ◽  
Lauren Mahoney ◽  
Cenk Suphioglu
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Neuronal Cells ◽  
Hdac Inhibitors ◽  
Histone Acetyltransferases ◽  
Human Neuronal Cells ◽  
The Brain

AbstractHistone acetyltransferases (HATs) and histone deacetylases (HDACs) promote histone posttranslational modifications, which lead to an epigenetic alteration in gene expression. Aberrant regulation of HATs and HDACs in neuronal cells results in pathological consequences such as neurodegeneration. Alzheimer’s disease is the most common neurodegenerative disease of the brain, which has devastating effects on patients and loved ones. The use of pan-HDAC inhibitors has shown great therapeutic promise in ameliorating neurodegenerative ailments. Recent evidence has emerged suggesting that certain deacetylases mediate neurotoxicity, whereas others provide neuroprotection. Therefore, the inhibition of certain isoforms to alleviate neurodegenerative manifestations has now become the focus of studies. In this review, we aimed to discuss and summarize some of the most recent and promising findings of HAT and HDAC functions in neurodegenerative diseases.

scholarly journals Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2558-2571 ◽  
Author(s):  
Matthew J Betts ◽  
Evgeniya Kirilina ◽  
Maria C G Otaduy ◽  
Dimo Ivanov ◽  
Julio Acosta-Cabronero ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Locus Coeruleus ◽  
Disease Progression ◽  
Structural Features ◽  
Behavioural Symptoms ◽  
Non Invasive ◽  
Neurodegenerative Dementias ◽  
The Brain ◽  
In Vivo Assessment

Abstract Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

The Role of Mitochondria in the Genesis of Neuroaxonal Dystrophy in the Brains of Aging Mice

1975 ◽  
Vol 33 ◽  
pp. 372-373
Author(s):  
J.E. Johnson
Keyword(s):  
Electron Microscopy ◽  
Present Report ◽  
Light And Electron Microscopy ◽  
Dorsal Column ◽  
Neuroaxonal Dystrophy ◽  
Nucleus Gracilis ◽  
Dystrophic Axons ◽  
The Brain ◽  
Nucleus Cuneatus

Although neuroaxonal dystrophy (NAD) has been examined by light and electron microscopy for years, the nature of the components in the dystrophic axons is not well understood. The present report examines nucleus gracilis and cuneatus (the dorsal column nuclei) in the brain stem of aging mice.Mice (C57BL/6J) were sacrificed by aldehyde perfusion at ages ranging from 3 months to 23 months. Several brain areas and parts of other organs were processed for electron microscopy.At 3 months of age, very little evidence of NAD can be discerned by light microscopy. At the EM level, a few axons are found to contain dystrophic material. By 23 months of age, the entire nucleus gracilis is filled with dystrophic axons. Much less NAD is seen in nucleus cuneatus by comparison. The most recurrent pattern of NAD is an enlarged profile, in the center of which is a mass of reticulated material (reticulated portion; or RP).

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