RESUMEN
Most lysosomal storage disorders (LSDs) cause progressive neurodegeneration leading to early death. While the genetic defects that cause these disorders impact all cells of the body, neurons are particularly affected. This vulnerability may be explained by neuronal cells' critical dependence on the lysosomal degradative capacity, as they cannot use division to eliminate their waste. However, mounting evidence supports the extension of storage beyond lysosomes to other cellular compartments (mitochondria, plasma membrane and synapses) as a key event in pathogenesis. Impaired energy supply, oxidative stress, calcium imbalance, synaptic failure and glial alterations may all contribute to neuronal death and thus could be suitable therapeutic targets for these disorders. Here we review the pathological mechanisms underlying neurodegeneration in Niemann Pick diseases and therapeutic strategies developed in animal models and patients suffering from these devastating disorders. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
Asunto(s)
Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/terapia , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/terapia , Enfermedades de Niemann-Pick/patología , Enfermedades de Niemann-Pick/terapia , Animales , Humanos , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades de Niemann-Pick/metabolismoRESUMEN
Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases that mediate the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence or impaired function of individual saposins or the whole prosaposin gene lead to distinct LSDs due to the storage of different classes of sphingolipids. The pathological events leading to neuronal dysfunction induced by lysosomal storage of sphingolipids are as yet poorly defined. We have generated and characterised a Drosophila model of saposin deficiency that shows striking similarities to the human diseases. Drosophila saposin-related (dSap-r) mutants show a reduced longevity, progressive neurodegeneration, lysosomal storage, dramatic swelling of neuronal soma, perturbations in sphingolipid catabolism, and sensory physiological deterioration. Our data suggests a genetic interaction with a calcium exchanger (Calx) pointing to a possible calcium homeostasis deficit in dSap-r mutants. Together these findings support the use of dSap-r mutants in advancing our understanding of the cellular pathology implicated in saposin deficiency and related LSDs.
Asunto(s)
Modelos Animales de Enfermedad , Proteínas de Drosophila/deficiencia , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Saposinas/deficiencia , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Animales Modificados Genéticamente , Antiportadores/genética , Antiportadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Calcio/metabolismo , Ceramidas/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Homeostasis/fisiología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades Neurodegenerativas/patología , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/metabolismo , Neuronas/patología , Fenotipo , Saposinas/genética , Esfingosina/metabolismo , Análisis de SupervivenciaRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-ß in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Autofagia , Lisosomas/patología , Enfermedad de Alzheimer/metabolismo , Animales , Humanos , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/fisiopatología , Lisosomas/metabolismoRESUMEN
Here, we evaluate the mechanisms underlying the neurodevelopmental deficits in Drosophila and mouse models of lysosomal storage diseases (LSDs). We find that lysosomes promote the growth of neuromuscular junctions (NMJs) via Rag GTPases and mechanistic target of rapamycin complex 1 (MTORC1). However, rather than employing S6K/4E-BP1, MTORC1 stimulates NMJ growth via JNK, a determinant of axonal growth in Drosophila and mammals. This role of lysosomal function in regulating JNK phosphorylation is conserved in mammals. Despite requiring the amino-acid-responsive kinase MTORC1, NMJ development is insensitive to dietary protein. We attribute this paradox to anaplastic lymphoma kinase (ALK), which restricts neuronal amino acid uptake, and the administration of an ALK inhibitor couples NMJ development to dietary protein. Our findings provide an explanation for the neurodevelopmental deficits in LSDs and suggest an actionable target for treatment.
Asunto(s)
Drosophila melanogaster/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Lisosomas/metabolismo , MAP Quinasa Quinasa 4/genética , Complejos Multiproteicos/genética , Unión Neuromuscular/genética , Serina-Treonina Quinasas TOR/genética , Quinasa de Linfoma Anaplásico , Animales , Proteínas de Unión al Calcio , Proteínas en la Dieta/administración & dosificación , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/metabolismo , Regulación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Lisosomas/efectos de los fármacos , Lisosomas/patología , MAP Quinasa Quinasa 4/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Complejos Multiproteicos/metabolismo , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/metabolismo , Unión Neuromuscular/patología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/patología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70%) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal storage diseases are monogenic, clear genotype-phenotype correlations occur only in some cases. In this article, we present an overview on various factors and processes, both general and specific for certain disorders, that can significantly modulate expression of phenotypes in these diseases. On the basis of recent reports describing studies on both animal models and clinical data, we propose a hypothesis that efficiency of production of compounds that cannot be degraded due to enzyme deficiency might be especially important in modulation of phenotypes of patients suffering from lysosomal storage diseases.
Asunto(s)
Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Animales , Conducta/fisiología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Enzimas/genética , Enzimas/fisiología , Interacción Gen-Ambiente , Genotipo , Humanos , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/psicología , Lisosomas/enzimología , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/fisiología , Ratones , Ratones Noqueados , Modelos Biológicos , Neuronas/metabolismo , Penetrancia , FenotipoRESUMEN
BACKGROUND: The lysosomal-autophagocytic system diseases (LASDs) affect multiple body systems including the central nervous system (CNS). The progressive CNS pathology has its onset at different ages, leading to neurodegeneration and early death. METHODS: Literature review provided insight into the current clinical neurological findings, phenotypic spectrum, and pathogenic mechanisms of LASDs with primary neurological involvement. CONCLUSIONS: CNS signs and symptoms are variable and related to the disease-specific underlying pathogenesis. LAS dysfunction leads to diverse global cellular consequences in the CNS ranging from specific axonal and dendritic abnormalities to neuronal death. Pathogenic mechanisms for disease progression vary from impaired autophagy, massive storage, regional involvement, to end-stage inflammation. Some of these features are also found in adult neurodegenerative disorders, for example, Parkinson's and Alzheimer's diseases. Lack of effective therapies is a significant unmet medical need.
Asunto(s)
Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Trastornos Heredodegenerativos del Sistema Nervioso , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso , Animales , Progresión de la Enfermedad , Trastornos Heredodegenerativos del Sistema Nervioso/diagnóstico , Trastornos Heredodegenerativos del Sistema Nervioso/metabolismo , Trastornos Heredodegenerativos del Sistema Nervioso/patología , Humanos , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/diagnóstico , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patologíaRESUMEN
Lipid storage diseases, also known as the lipidoses, are a group of inherited metabolic disorders in which there is lipid accumulation in various cell types, including the central nervous system, because of the deficiency of a variety of enzymes. Over time, excessive storage can cause permanent cellular and tissue damage. The brain is particularly sensitive to lipid storage as the contents of the central nervous system must occupy uniform volume, and any increases in fluids or deposits will lead to pressure changes and interference with normal neurological function. In addition to primary lipid storage diseases, lysosomal storage diseases include the mucolipidoses (in which excessive amounts of lipids and carbohydrates are stored in the cells and tissues) and the mucopolysaccharidoses (in which abnormal glycosylated proteins cannot be broken down because of enzyme deficiency). Neurological dysfunction can be a manifestation of these conditions due to substrate deposition as well. This review will explore the modalities of neuroimaging that may have particular relevance to the study of the lipid storage disorder and their impact on elucidating aspects of brain function. First, the techniques will be reviewed. Next, the neuropathology of a few selected lipid storage disorders will be reviewed and the use of neuroimaging to define disease characteristics discussed in further detail. Examples of studies using these techniques will be discussed in the text.
Asunto(s)
Encéfalo/metabolismo , Encéfalo/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso , Imagen por Resonancia Magnética , Neuroimagen , Encéfalo/fisiopatología , Imagen de Difusión Tensora , Humanos , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/diagnóstico , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/fisiopatología , Espectroscopía de Resonancia Magnética/métodos , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Trastorno Peroxisomal/diagnóstico , ProtonesRESUMEN
There is a strong association between lysosome enzyme deficiencies and monogenic disorders resulting in lysosomal storage disease. Of the more than 75 characterized lysosomal proteins, two thirds are directly linked to inherited diseases of metabolism. Only one lysosomal storage disease, Niemann-Pick disease, is associated with impaired phospholipid metabolism. However, other phospholipases are found in the lysosome but remain poorly characterized. A recent exception is lysosomal phospholipase A2 (group XV phospholipase A2). Although no inherited disorder of lysosomal phospholipid metabolism has yet been associated with a loss of function of this lipase, this enzyme may be a target for an acquired form of lysosomal storage, drug induced phospholipidosis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
Asunto(s)
Aciltransferasas/metabolismo , Lipólisis/efectos de los fármacos , Lisofosfolípidos/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Monoglicéridos/metabolismo , Fosfolipasas A2/metabolismo , Proteínas/metabolismo , Xenobióticos/efectos adversos , Secuencia de Aminoácidos , Animales , Humanos , Cinética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/etiología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Datos de Secuencia Molecular , Enfermedades de Niemann-Pick/metabolismo , Enfermedades de Niemann-Pick/patología , Proteínas/agonistasRESUMEN
The role of astrocytes in neurodegenerative processes is increasingly appreciated. Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene. Using Cre/Lox mouse models, we found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of autophagic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo. Furthermore, in an ex vivo coculture assay, we observed that Sumf1(-/-) astrocytes failed to support the survival and function of wild-type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration. Compared with the astrocyte-specific deletion of Sumf1, the concomitant removal of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioral analysis of mice with astrocyte-specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed us to link a subset of neurological manifestations of MSD to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in MSD and that modulation of astrocyte function may impact disease course.
Asunto(s)
Astrocitos/patología , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Degeneración Nerviosa/patología , Neuronas/patología , Sulfatasas/genética , Animales , Comunicación Celular/fisiología , Supervivencia Celular/fisiología , Células Cultivadas , Cerebelo/patología , Corteza Cerebral/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Lisosomas/patología , Lisosomas/ultraestructura , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Microscopía Electrónica , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Neuronas/ultraestructura , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Células de Purkinje/patología , Células de Purkinje/ultraestructuraRESUMEN
The resident macrophages of the gastrointestinal tract represent the largest population of macrophages in the human body and are usually located in the subepithelial lamina propria. This strategic location guarantees a first-line defense to the huge numbers of potentially harmful bacteria and antigenic stimuli that are present in the intestinal lumen. In non-inflamed mucosa, macrophages phagocytose and kill microbes in the absence of an inflammatory response. However, in the event of an epithelial breach and/or microbial invasion, new circulating monocytes and lymphocytes will be recruited to the damaged area of the gut, which will result in the secretion of proinflammatory mediators and engage a protective inflammatory response. Although macrophages are usually not conspicuous in normal mucosal samples of the gut, they can easily be detected when they accumulate exogenous particulate material or endogenous substances or when they become very numerous. These events will mostly occur in pathologic conditions, and this review presents an overview of the diseases which are either mediated by or affecting the resident macrophages of the gut.
Asunto(s)
Tracto Gastrointestinal/patología , Mucosa Intestinal/patología , Macrófagos/patología , Infecciones por Actinomycetales/patología , Colon/patología , Tracto Gastrointestinal/inmunología , Humanos , Inflamación/patología , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/inmunología , Lipofuscina/metabolismo , Enfermedades por Almacenamiento Lisosomal/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Macrófagos/química , Macrófagos/inmunología , Malacoplasia/patología , Melanosis/patología , Mucinas/metabolismo , Rhodococcus equi , Enfermedad de Whipple/patología , Xantomatosis/diagnóstico , Xantomatosis/patologíaRESUMEN
Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X-linked lysosomal storage disorder, characterized by α-galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi-organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α-galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.
Asunto(s)
Angioqueratoma/etiología , Técnicas de Apoyo para la Decisión , Enfermedad de Fabry/patología , Piel/patología , Algoritmos , Biopsia/métodos , Dermoscopía , Enfermedad de Fabry/complicaciones , Femenino , Humanos , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/complicaciones , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Masculino , Microscopía ElectrónicaRESUMEN
Synaptic terminals are known to expand and contract throughout an animal's life. The physiological constraints and demands that regulate appropriate synaptic growth and connectivity are currently poorly understood. In previous work, we identified a Drosophila model of lysosomal storage disease (LSD), spinster (spin), with larval neuromuscular synapse overgrowth. Here we identify a reactive oxygen species (ROS) burden in spin that may be attributable to previously identified lipofuscin deposition and lysosomal dysfunction, a cellular hallmark of LSD. Reducing ROS in spin mutants rescues synaptic overgrowth and electrophysiological deficits. Synapse overgrowth was also observed in mutants defective for protection from ROS and animals subjected to excessive ROS. ROS are known to stimulate JNK and fos signaling. Furthermore, JNK and fos in turn are known potent activators of synapse growth and function. Inhibiting JNK and fos activity in spin rescues synapse overgrowth and electrophysiological deficits. Similarly, inhibiting JNK, fos, and jun activity in animals with excessive oxidative stress rescues the overgrowth phenotype. These data suggest that ROS, via activation of the JNK signaling pathway, are a major regulator of synapse overgrowth. In LSD, increased autophagy contributes to lysosomal storage and, presumably, elevated levels of oxidative stress. In support of this suggestion, we report here that impaired autophagy function reverses synaptic overgrowth in spin. Our data describe a previously unexplored link between oxidative stress and synapse overgrowth via the JNK signaling pathway.
Asunto(s)
Drosophila/crecimiento & desarrollo , Drosophila/metabolismo , Unión Neuromuscular/crecimiento & desarrollo , Unión Neuromuscular/metabolismo , Animales , Animales Modificados Genéticamente , Autofagia/genética , Autofagia/fisiología , Modelos Animales de Enfermedad , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Genes de Insecto , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Sistema de Señalización de MAP Quinasas , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Modelos Neurológicos , Mutación , Estrés Oxidativo , Factor de Transcripción AP-1/metabolismoRESUMEN
Approximately 50 inborn errors of metabolism known as lysosomal storage disorders have been discovered to date, most of which are due to a single mutation in a gene encoding a soluble lysosomal enzyme. Consequently, inadequate enzyme activity results in the accumulation of substrates for that enzyme, invariably accompanied by a wide variety of secondary pathological changes. Many of these conditions remain untreatable, and therefore, research into pathogenic processes and potential treatment strategies is intense. A key tool for researchers in this area is the availability of clinically relevant animal models in which to study disease manifestation and evaluate therapeutic outcomes. Large numbers of both naturally occurring and genetically modified animal models of neurodegenerative lysosomal storage disorders are in existence, with spontaneous models occurring in both large domestic (e.g., cat, dog, sheep) and small (e.g., mouse) animal species. Many have undergone rigorous phenotypic characterization and are now providing us with insights into neurological disease processes. The purpose of this review is to highlight some of the major lessons learnt from these studies.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/fisiopatología , Animales , Gatos , Perros , Humanos , Ratones , OvinosRESUMEN
Although neurodegenerative diseases are most prevalent in the elderly, in rare cases, they can also affect children. Lysosomal storage diseases (LSDs) are a group of inherited metabolic neurodegenerative disorders due to deficiency of a specific protein integral to lysosomal function, such as enzymes or lysosomal components, or to errors in enzyme trafficking/targeting and defective function of nonenzymatic lysosomal proteins, all preventing the complete degradation and recycling of macromolecules. This primary metabolic event determines a cascade of secondary events, inducing LSD's pathology. The accumulation of intermediate degradation affects the function of lysosomes and other cellular organelles. Accumulation begins in infancy and progressively worsens, often affecting several organs, including the central nervous system (CNS). Affected neurons may die through apoptosis or necrosis, although neuronal loss usually does not occur before advanced stages of the disease. CNS pathology causes mental retardation, progressive neurodegeneration, and premature death. Many of these features are also found in adult neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. However, the nature of the secondary events and their exact contribution to mental retardation and dementia remains largely unknown. Recently, lysosomal involvement in the pathogenesis of these disorders has been described. Improved knowledge of secondary events may have impact on diagnosis, staging, and follow-up of affected children. Importantly, new insights may provide indications about possible disease reversal upon treatment. A discussion about the CNS pathophysiology involvement in LSDs is the aim of this review. The lysosomal involvement in adult neurodegenerative diseases will also be briefly described.
Asunto(s)
Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/fisiopatología , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , HumanosRESUMEN
Lysosomal disease represents a large group of more than 50 clinically recognized conditions resulting from inborn errors of metabolism affecting the organelle known as the lysosome. The lysosome is an integral part of the larger endosomal/lysosomal system, and is closely allied with the ubiquitin-proteosomal and autophagosomal systems, which together comprise essential cell machinery for substrate degradation and recycling, homeostatic control, and signalling. More than two-thirds of lysosomal diseases affect the brain, with neurons appearing particularly vulnerable to lysosomal compromise and showing diverse consequences ranging from specific axonal and dendritic abnormalities to neuron death. While failure of lysosomal function characteristically leads to lysosomal storage, new studies argue that lysosomal diseases may also be appropriately viewed as 'states of deficiency' rather than simply overabundance (storage). Interference with signalling events and salvage processing normally controlled by the endosomal/lysosomal system may represent key mechanisms accounting for the inherent complexity of lysosomal disorders. Analysis of lysosomal disease pathogenesis provides a unique window through which to observe the importance of the greater lysosomal system for normal cell health.
Asunto(s)
Enfermedades por Almacenamiento Lisosomal/patología , Humanos , Enfermedades por Almacenamiento Lisosomal/genética , Enfermedades por Almacenamiento Lisosomal/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Lisosomas/metabolismo , Lisosomas/fisiología , Neuroglía/patología , Neuronas/patología , Proteínas/metabolismo , Transducción de Señal/fisiologíaRESUMEN
A subgroup of neutral lipid storage disease has been recently associated with myopathy (NLSDM) and attributed to mutations in the gene (PNPLA2) encoding an adipose triglyceride lipase involved in the degradation of intracellular triglycerides. Five NLSDM patients have been described thus far and we reported three additional patients. A 44-year old Iranian woman and two Italian brothers, aged 40 and 35, presented with exercise intolerance and proximal limb weakness, elevated CK levels, and Jordan's anomaly. Muscle biopsies showed marked neutral lipid accumulation in all patients. The 10 exons and the intron-exon junctions of the PNPLA2 gene were sequenced. Two novel homozygous mutations in exon 5 of PNPLA2 gene were found (c.695delT and c.542delAC). Both mutations resulted in frameshifts leading to premature stop codons (p.L255X and p.I212X, respectively). These mutations predict a truncated PNPLA2 protein lacking the C-terminal hydrophobic domain. These findings indicate that NLSDM is rare, but genetically heterogeneous.
Asunto(s)
Mutación del Sistema de Lectura , Lipasa/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Enfermedades Musculares/genética , Adulto , Biopsia , Exones/genética , Femenino , Humanos , Lipasa/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patologíaRESUMEN
Danon disease is an X-linked cardioskeletal myopathy, originally reported as "lysosomal glycogen storage disease with normal acid maltase," resulting from a primary deficiency of lysosome-associated membrane protein-2 because of mutations in the lysosome-associated membrane protein-2 gene. Classic clinical features in males include cardiomyopathy (100%, eventually), myopathy (90%), and mental retardation (70%), but mostly of a mild degree. We report on an unusual presentation in a patient with autism, motor delay, and a normal cardiac evaluation. The presence of multiorgan involvement, including elevated liver enzymes, abnormal cranial magnetic resonance imaging, and diffuse hypotonia with swallowing difficulties, prompted a muscle biopsy. A quadriceps muscle biopsy was performed, and the findings were most suspicious for a glycogen storage-type disease. Subsequently, a pathogenic lysosome-associated membrane protein-2 mutation was found. To our knowledge, there are no previous clinical reports of autism in children with Danon disease.
Asunto(s)
Trastorno Autístico/etiología , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Enfermedad por Depósito de Glucógeno de Tipo IIb/complicaciones , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades Musculares/patología , Trastorno Autístico/psicología , Encéfalo/patología , Enfermedades Genéticas Ligadas al Cromosoma X/psicología , Enfermedad por Depósito de Glucógeno de Tipo IIb/psicología , Humanos , Lactante , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/psicología , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/patología , Enfermedades Musculares/psicología , SíndromeRESUMEN
Most lysosomal storage disorders are characterized by progressive central nervous system impairment, with or without systemic involvement. Affected individuals have an array of symptoms related to brain dysfunction, the most devastating of which is neurodegeneration following a period of normal development. The blood-brain barrier has represented a significant impediment to developing therapeutic approaches to treat brain disease, but novel approaches-including enzyme replacement, small-molecule, gene, and cell-based therapies-have given children afflicted by these conditions and those who care for them hope for the future.
Asunto(s)
Sistema Nervioso Central/fisiopatología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/terapia , Animales , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Sistema Nervioso Central/enzimología , Sistema Nervioso Central/patología , Sistema Nervioso Central/cirugía , Terapia Genética/métodos , Humanos , Hidrolasas/uso terapéutico , Lisosomas/enzimología , Lisosomas/genética , Lisosomas/patologíaRESUMEN
Most lysosomal storage disorders (LSDs) are caused by deficiencies of lysosomal hydrolases. While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood. Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion. An impairment of the autophagic pathway was demonstrated by the inefficient degradation of exogenous aggregate-prone proteins (i.e. expanded huntingtin and mutated alpha-synuclein) in cells from LSD mice. This impairment resulted in massive accumulation of polyubiquitinated proteins and of dysfunctional mitochondria which are the putative mediators of cell death. These data identify LSDs as 'autophagy disorders' and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.
Asunto(s)
Autofagia/fisiología , Enfermedades por Almacenamiento Lisosomal/patología , Animales , Autofagia/genética , Secuencia de Bases , Células Cultivadas , Cartilla de ADN/genética , Humanos , Enfermedades por Almacenamiento Lisosomal/genética , Enfermedades por Almacenamiento Lisosomal/fisiopatología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/fisiopatología , Lisosomas/patología , Fusión de Membrana , Ratones , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/patología , Mucopolisacaridosis III/genética , Mucopolisacaridosis III/patología , Mucopolisacaridosis III/fisiopatología , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Enfermedad por Deficiencia de Múltiples Sulfatasas/fisiopatología , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Fagosomas/patología , Transfección , UbiquitinaciónRESUMEN
It is estimated that more than 40 different lysosomal storage disorders (LSDs) cumulatively affect one in 5000 live births, and in the majority of the LSDs, neurodegeneration is a prominent feature. Neuronal ceroid lipofuscinoses (NCLs), as a group, represent one of the most common (one in 12,500 births) neurodegenerative LSDs. The infantile NCL (INCL) is the most devastating neurodegenerative LSD, which is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. We previously reported that neuronal death by apoptosis in INCL, and in the PPT1-knockout (PPT1-KO) mice that mimic INCL, is at least in part caused by endoplasmic reticulum (ER) and oxidative stresses. In the present study, we sought to determine whether ER and oxidative stresses are unique manifestations of INCL or they are common to both neurodegenerative and non-neurodegenerative LSDs. Unexpectedly, we found that ER and oxidative stresses are common manifestations in cells from both neurodegenerative and non-neurodegenerative LSDs. Moreover, all LSD cells studied show extraordinary sensitivity to brefeldin-A-induced apoptosis, which suggests pre-existing ER stress conditions. Further, we uncovered that chemical disruption of lysosomal homeostasis in normal cells causes ER stress, suggesting a cross-talk between the lysosomes and the ER. Most importantly, we found that chemical chaperones that alleviate ER and oxidative stresses are also cytoprotective in all forms of LSDs studied. We propose that ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative LSDs and suggest that the beneficial effects of chemical/pharmacological chaperones are exerted, at least in part, by alleviating these stress conditions.