Superoxide Dismutase, Mitochondrial Dysfunction, and Neurodegenerative Diseases
Excessive amounts of reactive oxygen/nitrogen species (ROS/RNS), e.g. hydroxyl radical (•OH) and peroxynitrite (ONOO–), wreak oxidative havoc in cells by causing DNA strand breaks, crosslinking or fragmentation of proteins and peroxidation of lipids. Oxidation is especially damaging to mitochondria, the source of energy for cells. Interestingly, mitochondria are also the largest source of ROS/RNS in cells. Superoxide (O2 •–), produced as a byproduct to energy production by the mitochondrial electron transport chain (ETC), is capable of directly damaging the mitochondria, and also serves as a precursor to more powerful ROS and RNS, such as •OH and ONOO–. Superoxide dismutases (SODs) are the first line of defense in combating this oxidative damage by converting O2 •– into oxygen (O2) and hydrogen peroxide (H2O2). Manganese SOD (MnSOD) resides within the mitochondrial matrix while intracellular copper-zinc SOD (CuZnSOD) resides in the mitochondrial intermembrane space (MIMS) and cytosol. The enzymatic function of these SODs is paramount to preserving the mitochondria and its energy production. Despite their biological importance, the enzymatic mechanism of SODs is still unclear. SODs perform their function through highly efficient proton-coupled electron transfers (PCETs) that are extremely difficult to detect. Dysfunction of either MnSOD or CuZnSOD can lead to mitochondrial degeneration, a characteristic of neurodegenerative pathologies such as Alzheimer’s disease (AD), Parkinson’s disease and amyotrophic lateral sclerosis (ALS). Here, we review the mitochondrial damage caused by ROS/RNS, current insights into the mysterious catalytic mechanism of SODs, and how neurodegenerative pathologies develop when SODs become dysfunctional.
Pantothenate Kinase-Associated Neurodegeneration (PKAN)
Pantothenate kinase-associated neurodegeneration (PKAN) is a genetic movement disorder that accounts for the majority of cases of what was formerly called Hallervorden-Spatz syndrome. In 1922, Hallervorden and Spatz reported an autosomal recessive neurodegenerative disorder with retinitis pigmentosa and high levels of iron in brain. Since then, the diagnosis has been expanded to encompass a heterogeneous group of disorders that share the feature of high brain iron. To discredit Hallervorden and Spatz for their objectionable actions during World War II, the eponym has been abandoned and replaced with the term ‘‘neurodegeneration with brain iron accumulation’’ (NBIA). NBIA includes neurological disorders in which basal ganglia iron levels are high. PKAN is one form of NBIA.
Social cognition in neurodegenerative diseases
Social cognition is impacted in patients with Huntington’s disease (HD), Parkinson’s disease (PD) and multiple sclerosis (MS) as a consequence of neuropathology involving subcortical regions of the brain as well as the neural connections of frontal-striatal networks. A large body of research suggests that difficulties in emotion perception are an important feature of all three disorders. Although this impairment is most documented in facial emotion recognition tasks, impairments have also been identified in other modalities, such as vocal prosody and body language. While the mechanisms of impaired emotion perception in HD, PD and MS remain unclear, a number of possible mechanisms have been the subject of research, including general cognitive decline, face processing abilities, motor impairment and neuropsychiatric syndromes that affect general emotional functioning. Impairments in theory of mind in both the cognitive and affective domains have also been well documented across all three disorders, and cognitive ToM deficits have been frequently linked to impairments in executive function. Importantly, the ecological validity of common measures of emotion perception and ToM have been questioned, and further research is needed to determine the psychosocial outcomes of impaired social cognition in HD, PD and MS.
Unilateral Ex Vivo Gene Therapy by GDNF in Neurodegenerative Diseases
Gene therapy is a powerful therapeutic strategy in various neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). To achieve a satisfactory therapeutic effect, several steps has been taken in clinical trials and laboratory-based animal models. Delivery of neurotropic factor to the brain has been shown to be efficacious in various models of neurodegenerative diseases which effectively reduces the neuronal loss, hence repairing the brain function. Unilateral ex vivo and in vivo delivery of glial cell line–derived neurotropic factor (GDNF) produces a potential neuroprotective effect in various neurodegenerative disorders such as the activity of dopaminergic neurons and expression of certain proteins or genes associated with AD and HD. Apart from this, numerous investigations are currently working to accomplish the desired therapeutic effect of GDNF after administration, with minimal adverse effects. Efforts are also underway to enhance effectiveness by incorporating reliable delivery routes and vectors, such as viral vectors, to attain an ultimately powerful treatment for patients with brain injury or neurodegenerative diseases.
Studies of neurodegenerative diseases using Drosophila and the development of novel approaches for their analysis
Published in Fly
The use of Drosophila in neurodegenerative disease research has contributed to the identification of modifier genes for the pathology. The basis for neurodegenerative disease occurrence in Drosophila is the conservation of genes across species and the ability to perform rapid genetic analysis using a compact brain. Genetic findings previously discovered in Drosophila can reveal molecular pathologies involved in human neurological diseases in later years. Disease models using Drosophila began to be generated during the development of genetic engineering. In recent years, results of reverse translational research using Drosophila have been reported. In this review, we discuss research on neurodegenerative diseases; moreover, we introduce various methods for quantifying neurodegeneration in Drosophila.
Is SARS-CoV-2 vaccination safe and effective for elderly individuals with neurodegenerative diseases?
Published in Expert Review of Vaccines
Coronavirus Disease 2019 (COVID-19) poses a substantial threat to the lives of the elderly, especially those with neurodegenerative diseases, and vaccination against viral infections is recognized as an effective measure to reduce mortality. However, elderly patients with neurodegenerative diseases often suffer from abnormal immune function and take multiple medications, which may complicate the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. Currently, there is no expert consensus on whether SARS-CoV-2 vaccines are suitable for patients with neurodegenerative diseases.
Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders
Published in Neurological Research
Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body’s antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich’s ataxia, Huntington’s disease, Multiple sclerosis, and Parkinson’s diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.
Food for thought: the emerging role of a ketogenic diet in Alzheimer’s disease management
Published in Expert Review of Neurotherapeutics
Alzheimer disease (AD) is the leading cause of dementia in aging societies worldwide. A complex interaction of multiple mechanisms and neurodegenerative processes leads to the development of AD, and the initial pathological process may start as long as 20 years before its clinical manifestation. Currently, available therapies are still ineffective [Citation1]. Therefore, the search for AD prevention and treatment methods also includes dietary modifications. Research indicates the potential importance of specific food components in preventing and managing AD, such as omega-3 fatty acids, vitamins B and E, choline, and uridine. However, clinical evidence on whether nutritional supplementation prevents AD onset or progression is still lacking. Thus, alternative strategies based on dietary patterns seem to be more valuable and promising than focusing on single food components. Recently, particular attention has been paid to the possible function of three dietary patterns in AD prevention: the Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet, and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. These dietary patterns have well-known anti-inflammatory and antioxidant properties, and their neuroprotective properties have been shown to be related to their high bioactive compound content. Further, based on animal models in AD studies, intermittent fasting and calorie restriction are emerging as new approaches that appear to lead to motor and cognitive improvements by promoting hippocampal neurogenesis, activating adaptive stress response systems, and enhancing neuronal plasticity [Citation2].
Neurodegeneration in multiple sclerosis involves multiple pathogenic mechanisms
Published in Degenerative Neurological and Neuromuscular Disease
Multiple sclerosis (MS) is a complex autoimmune disease that impairs the central nervous system (CNS). The neurological disability and clinical course of the disease is highly variable and unpredictable from one patient to another. The cause of MS is still unknown, but it is thought to occur in genetically susceptible individuals who develop disease due to a nongenetic trigger, such as altered metabolism, a virus, or other environmental factors. MS patients develop progressive, irreversible, neurological disability associated with neuronal and axonal damage, collectively known as neurodegeneration. Neurodegeneration was traditionally considered as a secondary phenomenon to inflammation and demyelination. However, recent data indicate that neurodegeneration develops along with inflammation and demyelination. Thus, MS is increasingly recognized as a neurodegenerative disease triggered by an inflammatory attack of the CNS. While both inflammation and demyelination are well described and understood cellular processes, neurodegeneration might be defined by a diverse pool of any of the following: neuronal cell death, apoptosis, necrosis, and virtual hypoxia. In this review, we present multiple theories and supporting evidence that identify common biological processes that contribute to neurodegeneration in MS.
Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease
Published in Neuropsychiatric Disease and Treatment
Purpose: Parkinson’s disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model.