Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases

Cytoplasmic dynein is the most important molecular motor driving the movement of a wide range of cargoes towards the minus ends of microtubules.As a molecular motor protein,dynein performs a variety of basic cellular functions including organelle transport and centrosome assembly.In the nervous system,dynein has been demonstrated to be responsible for axonal retrograde transport.Many studies have revealed direct or indirect evidence of dynein in neurodegenerative diseases such as amyotrophic lateral sclerosis,Charcot-Marie-Tooth disease,Alzheimer’s disease,Parkinson’s disease and Huntington’s disease.Among them,a number of mutant proteins involved in various neurodegenerative diseases interact with dynein.Axonal transport disruption is presented as a common feature occurring in neurodegenerative diseases.Dynein heavy chain mutant mice also show features of neurodegenerative diseases.Moreover,defects of dynein-dependent processes such as autophagy or clearance of aggregation-prone proteins are found in most of these diseases.Lines of evidence have also shown that dynein is associated with neurodevelopmental diseases.In this review,we focus on dynein involvement in different neurological diseases and discuss potential underlying mechanisms.     

Possible involvement of transglutaminase-catalyzed reactions in the physiopathology of neurodegenerative diseases

Transglutaminases are ubiquitous enzymes, which catalyze post-translational modifications of proteins. Recently, transglutaminases and tranglutaminase-catalyzed post-translational modification of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for human neurodegenerative diseases. Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, supranuclear palsy, Huntington’s disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. In this review, we focus on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of neurodegenerative diseases, and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity.     

Nature, nurture and neurology: gene-environment interactions in neurodegenerative disease. FEBS Anniversary Prize Lecture delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw

Neurodegenerative disorders, such as Huntington's, Alzheimer's, and Parkinson's diseases, affect millions of people worldwide and currently there are few effective treatments and no cures for these diseases. Transgenic mice expressing human transgenes for huntingtin, amyloid precursor protein, and other genes associated with familial forms of neurodegenerative disease in humans provide remarkable tools for studying neurodegeneration because they mimic many of the pathological and behavioural features of the human conditions. One of the recurring themes revealed by these various transgenic models is that different diseases may share similar molecular and cellular mechanisms of pathogenesis. Cellular mechanisms known to be disrupted at early stages in multiple neurodegenerative disorders include gene expression, protein interactions (manifesting as pathological protein aggregation and disrupted signaling), synaptic function and plasticity. Recent work in mouse models of Huntington's disease has shown that enriching the environment of transgenic animals delays the onset and slows the progression of Huntington's disease-associated motor and cognitive symptoms. Environmental enrichment is known to induce various molecular and cellular changes in specific brain regions of wild-type animals, including altered gene expression profiles, enhanced neurogenesis and synaptic plasticity. The promising effects of environmental stimulation, demonstrated recently in models of neurodegenerative disease, suggest that therapy based on the principles of environmental enrichment might benefit disease sufferers and provide insight into possible mechanisms of neurodegeneration and subsequent identification of novel therapeutic targets. Here, we review the studies of environmental enrichment relevant to some major neurodegenerative diseases and discuss their research and clinical implications.     

Neurodegenerative Diseases: Pathology and the Advantage of Single-Cell Profiling

The aggregation of neuronal proteins as inclusions is emerging as a common mechanistic theme in neurodegenerative diseases. The presence of these "disease-specific" pathologic changes in the brains of patients with neurodegenerative diseases assist pathologists in the diagnosis and characterization of dementing illnesses. However, these same inclusions may provide valuable clues toward understanding common pathologic roots and shared abnormalities in protein folding across disorders. Such an investigation will likely provide insights into disease mechanisms underlying neurodegenerative disorders characterized by abundant filamentous lesions. This review focuses on two themes: (i) Neurodegenerative disorders are characterized by shared and distinct histopathological and biochemical abnormalities, and (ii) the presence of abnormal protein aggregates may alter a gene, and hence protein expression in inclusion-bearing neurons predisposes them to dysfunction and eventual neuronal degeneration. The pathologic features of neurodegenerative diseases are first discussed followed by a rationale behind sampling mRNA species from single cells rather than from whole-brain homogenates to explore disease mechanisms.     

Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease

Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders.     

Protein misfolding in the late‐onset neurodegenerative diseases: Common themes and the unique case of amyotrophic lateral sclerosis

Enormous strides have been made in the last 100 years to extend human life expectancy and to combat the major infectious diseases. Today, the major challenges for medical science are age‐related diseases, including cancer, heart disease, lung disease, renal disease, and late‐onset neurodegenerative disease. Of these, only the neurodegenerative diseases represent a class of disease so poorly understood that no general strategies for prevention or treatment exist. These diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, the transmissible spongiform encephalopathies, and amyotrophic lateral sclerosis (ALS), are generally fatal and incurable. The first section of this review summarizes the diversity and common features of the late‐onset neurodegenerative diseases, with a particular focus on protein misfolding and aggregation—a recurring theme in the molecular pathology. The second section focuses on the particular case of ALS, a late‐onset neurodegenerative disease characterized by the death of central nervous system motor neurons, leading to paralysis and patient death. Of the 10% of ALS cases that show familial inheritance (familial ALS), the largest subset is caused by mutations in the SOD1 gene, encoding the Cu, Zn superoxide dismutase (SOD1). The unusual kinetic stability of SOD1 has provided a unique opportunity for detailed structural characterization of conformational states potentially involved in SOD1‐associated ALS. This review discusses past studies exploring the stability, folding, and misfolding behavior of SOD1, as well as the therapeutic possibilities of using detailed knowledge of misfolding pathways to target the molecular mechanisms underlying ALS and other neurodegenerative diseases. Proteins 2013; 81:1285–1303. © 2013 Wiley Periodicals, Inc.     

溶酶体离子通道蛋白在神经退行性疾病发生发展中的作用及机制研究

溶酶体离子通道蛋白异常引起溶酶体功能障碍是导致阿尔茨海默病(Alzheimer’s disease,AD)和帕金森病(Parkinson’s disease,PD)等神经退行性疾病的重要因素.溶酶体离子通道蛋白调节溶酶体内离子稳态、溶酶体膜电压以及溶酶体的酸度.溶酶体离子通道蛋白的结构或功能缺陷会引起溶酶体降解功能障碍,导致神经退行性疾病的发生发展.在这篇综述中,我们总结了各种离子通道蛋白调节溶酶体功能的过程及机制,以及离子通道蛋白异常参与神经退行性疾病的过程和机制.调节离子通道蛋白改善溶酶体的功能、促进异常聚集蛋白的清除,是神经退行性疾病治疗的潜在途径.     

Molecular mediators, environmental modulators and experience-dependent synaptic dysfunction in Huntington's disease

Huntington's disease (HD) is an autosomal dominant disorder in which there is progressive neurodegeneration producing motor, cognitive and psychiatric symptoms. HD is caused by a trinucleotide (CAG) repeat mutation, encoding an expanded polyglutamine tract in the huntingtin protein. At least eight other neurodegenerative diseases are caused by CAG/glutamine repeat expansions in different genes. Recent evidence suggests that environmental factors can modify the onset and progression of Huntington's disease and possibly other neurodegenerative disorders. This review outlines possible molecular and cellular mechanisms mediating the polyglutamine-induced toxic 'gain of function' and associated gene-environment interactions in HD. Key aspects of pathogenesis shared with other neurodegenerative diseases may include abnormal protein-protein interactions, selective disruption of gene expression and 'pathological plasticity' of synapses in specific brain regions. Recent discoveries regarding molecular mechanisms of pathogenesis are guiding the development of new therapeutic approaches. Knowledge of gene-environment interactions, for example, could lead to development of 'enviromimetics' which mimic the beneficial effects of specific environmental stimuli. The effects of environmental enrichment on brain and behaviour will also be discussed, together with the general implications for neuroscience research involving animal models.     

Modeling synucleinopathies in genetically modified animals: Successes and failures

The synuclein family and particularly α-synuclein takes a central part in aetiology and pathogenesis of Parkinson’s disease—one of the most common human neurodegenerative diseases. The pathological changes in certain other neurodegenerative diseases are also linked to changes in the metabolism and function of α-synuclein, hence comprising a new group of diseases—synucleinopathies. The molecular and cellular mechanisms that are involved in the development of neurodegeneration in synucleinopathies are still largely unknown. As a result, the therapeutic approaches to the treatment of synucleinopathies are inadequately tampered. The development of models of neurodegenerative process in laboratory animals plays a crucial role in the study of these molecular mechanisms. Recently a special emphasis was placed on transgenic animal models with modified expression of genes, whose mutations are associated with inherited forms of human neurodegenerative diseases. The current review is devoted to the analysis of different models of synucleinopathies as a result of genetic modifications of α-synuclein expression.     

Cholesterol metabolism and homeostasis in the brain

Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to bloodbrain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.     

Regulation of membrane dynamics by Parkinson’s disease-associated genes

Parkinson’s disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, develops sporadically, and its cause is unknown. However, 5–10% of PD cases are inherited as monogenic diseases, which provides a chance to understand the molecular mechanisms underlying neurodegeneration. Over 20 causative genes have already been identified and are being characterized. These PD-associated genes are broadly classified into two groups: genes involved in mitochondrial functions and genes related to membrane dynamics such as intracellular vesicle transport and the lysosomal pathway. In this review, we summarize the latest findings on the mechanism by which members of the latter group of PD-associated genes regulate membrane dynamics, and we discuss how mutations of these genes lead to dopaminergic neurodegeneration.     

The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease

The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age‐related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS‐related therapies for AD.     

Manganese neurotoxicity: A bioinorganic chemist’s perspective

Manganese is an essential metal for life, yet chronic exposure to this metal can cause a neurodegenerative disease named manganism, with symptoms that resemble Parkinson’s disease. Mn accumulates in the striatum and damages this brain structure that controls motor function; however, the molecular mechanisms underlying this neurodegenerative disease are poorly understood. In this short review, a summary of the current knowledge on the mechanisms involved in Mn neurotoxicity is given, with a special emphasis on the features that suggest specific protein-manganese interactions. The mechanisms of Mn uptake into the brain are discussed, displaying its similarities to Fe metabolism. Cellular trafficking of Mn is also reviewed, pointing out at its connection to Ca homeostasis, and its relevance for understanding Mn-induced neuronal death. The main purpose of this review is to provide a glimpse of an unexplored bioinorganic facet of a Mn-induced neurodegenerative disease.     

Proteomic analysis of mitochondrial dysfunction in neurodegenerative diseases

Alzheimer’s, Parkinson’s and Huntington’s disease, and amyotrophic lateral sclerosis are the most relevant neurodegenerative syndromes worldwide. The identification of the etiology and additional factors contributing to the onset and progression of these diseases is of great importance in order to develop both preventive and therapeutic intervention. A common feature of these pathologies is the formation of aggregates, containing mutated and/or misfolded proteins, in specific subsets of neurons, which progressively undergo functional impairment and die. The relationship between protein aggregation and the molecular events leading to neurodegeneration has not yet been clarified. In the last decade, several lines of evidence pointed to a major role for mitochondrial dysfunction in the onset of these pathologies. Here, we review how proteomics has been applied to neurodegenerative diseases in order to characterize the relationship existing between protein aggregation and mitochondrial alterations. Moreover, we highlight recent advances in the use of proteomics to identify protein modifications caused by oxidative stress. Future developments in this field are expected to significantly contribute to the full comprehension of the molecular mechanisms at the heart of neurodegeneration.     

Association Between Pathophysiological Mechanisms of Diabetic Retinopathy and Parkinson’s Disease

Diabetic retinopathy, the most common complication of diabetes, is a neurodegenerative disease in the eye. And Parkinson's disease, affecting the health of 1–2% of people over 60 years old throughout the world, is the second largest neurodegenerative disease in the brain. As the understanding of diabetic retinopathy and Parkinson's disease deepens, the two diseases are found to show correlation in incidence, similarity in clinical presentation, and close association in pathophysiological mechanisms. To reveal the association between pathophysiological mechanisms of the two disease, in this review, the shared pathophysiological factors of diabetic retinopathy and Parkinson's disease are summarized and classified into dopaminergic system, circadian rhythm, neurotrophic factors, α-synuclein, and Wnt signaling pathways. Furthermore, similar and different mechanisms so far as the shared pathophysiological factors of the two disorders are discussed systematically. Finally, a brief summary and new perspectives are presented to provide new directions for further efforts on the association, exploration, and clinical prevention and treatment of diabetic retinopathy and Parkinson's disease.

     

Polyphenolic compounds for treating neurodegenerative disorders involving protein misfolding

A diverse group of neurodegenerative diseases are characterized by progressive, age-dependent intracellular formation of misfolded protein aggregates. These include Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and a number of tau-mediated disorders. There is no effective treatment for any of these disorders; currently approved interventions are designed to treat disease symptoms and generally lead to modest modulation of clinical symptoms. None are known to mitigate underlying neuropathologic mechanisms and, thus, it is not unexpected that existing treatments appear ineffective in modulating disease progression. We note that these neurodegenerative disorders all share a common mechanistic theme in that depositions of misfolded protein in the brain is a key molecular feature underlying disease onset and/or progression. While previous studies have identified a number of drugs and nutraceuticals capable of interfering with the formation and/or stability of misfolded protein aggregates, none have been demonstrated to be effective in vivo for treating any of the neurodegenerative disorders. We hereby review accumulating evidence that a select nutraceutical grape-seed polyphenolic extract (GSPE) is effective in vitro and in vivo in mitigating certain misfolded protein-mediated neuropathologic and clinical phenotypes. We will also review evidence implicating bioavailability of GSPE components in the brain and the tolerability as well as safety of GSPE in animal models and in humans. Collectively, available information supports continued development of the GSPE for treating a variety of neurodegenerative disorders involving misfolded protein-mediated neuropathologic mechanisms.     

Adrenomedullin,a Novel Target for Neurodegenerative Diseases

Neurodegenerative diseases represent a heterogeneous group of disorders whose common characteristic is the progressive degeneration of neuronal structure and function. Although much knowledge has been accumulated on the pathophysiology of neurodegenerative diseases over the years, more efforts are needed to understand the processes that underlie these diseases and hence to propose new treatments. Adrenomedullin (AM) is a multifunctional peptide involved in vasodilation, hormone secretion, antimicrobial defense, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins that interfere with microtubule dynamics. Furthermore, AM may intervene in neuronal dysfunction through other mechanisms such as immune and inflammatory response, apoptosis, or calcium dyshomeostasis. Alterations in AM expression have been described in neurodegenerative processes such as Alzheimer’s disease or vascular dementia. This review addresses the current state of knowledge on AM and its possible implication in neurodegenerative diseases.     

Out of Balance: R-loops in Human Disease

R-loops are cellular structures composed of an RNA/DNA hybrid, which is formed when the RNA hybridises to a complementary DNA strand and a displaced single-stranded DNA. R-loops have been detected in various organisms from bacteria to mammals and play crucial roles in regulating gene expression, DNA and histone modifications, immunoglobulin class switch recombination, DNA replication, and genome stability. Recent evidence suggests that R-loops are also involved in molecular mechanisms of neurological diseases and cancer. In addition, mutations in factors implicated in R-loop biology, such as RNase H and SETX (senataxin), lead to devastating human neurodegenerative disorders, highlighting the importance of correctly regulating the level of R-loops in human cells. In this review we summarise current advances in this field, with a particular focus on diseases associated with dysregulation of R-loop structures. We also discuss potential therapeutic approaches for such diseases and highlight future research directions.