Clarifying lysosomal storage diseases

Lysosomal storage diseases (LSDs) are a class of metabolic disorders caused by mutations in proteins critical for lysosomal function. Such proteins include lysosomal enzymes, lysosomal integral membrane proteins, and proteins involved in the post-translational modification and trafficking of lysosomal proteins. There are many recognized forms of LSDs and, although individually rare, their combined prevalence is estimated to be 1 in 8000 births. Over two-thirds of LSDs involve central nervous system (CNS) dysfunction (progressive cognitive and motor decline) and these symptoms are often the most debilitating. Although the genetic basis for these disorders is clear and the biochemistry of the proteins well understood, the cellular mechanisms by which deficiencies in these proteins disrupt neuronal viability remain ambiguous. In this review, we provide an overview of the widespread cellular perturbations occurring in LSDs, how they might be linked and interventions that may specifically or globally correct those defects.     

Molecular heterogeneity in lysosomal storage diseases

Molecular and chemical neuropathology - The availability of specific antibodies and cDNA probes for lysosomal hydrolases has revealed unexpected heterogeneity among the human inherited lysosomal...     

Intraepidermal morphologic manifestations in lysosomal diseases

This paper reports the ultrastructural findings for the epidermis of biopsied skin specimens in numerous lysosomal diseases, which can be grouped as follows: a) presence of vacuolar lysosomal residual bodies in mucopolysaccharidoses I, II and III, Salla disease, GM1-gangliosidoses and infantile type II glycogenosis; b) avacuolar lysosomal residual bodies in Niemann-Pick disease type C, mucolipidosis IV, Farber disease, Fabry disease, and late infantile and juvenile neuronal ceroid-lipofuscinoses; c) absence of lysosomal residual bodies in GM2-gangliosidoses, metachromatic leukodystrophy, Gaucher disease and sialidosis type III. Whenever possible, a biopsy of the skin for morphological diagnosis of lysosomal disorders ought not to be confined to the epidermis.     

Sulfated glycosaminoglycans in amyloid plaques of prion diseases

Summary Brain sections from cases of human Creutzfeldt-Jakob disease, Gerstmann-Sträussler syndrome, kuru, and hamster scrapie containing amyloid were examined for the presence of sulfated glycosaminoglycans (GAGs), the anionic component of proteoglycans, using the sulfated Alcian blue method and Alcian blue technique with 0.3 M and 0.7 M magnesium chloride. These studies suggest that sulfated glycosaminoglycans are part of the CNS amyloid plaques in each of the above human prion disorders as well as in experimental scrapie. All the amyloid plaques stained positively with Alcian blue at 0.3 M, and less so at 0.7 M magnesium chloride indicating the presence of sulfated GAGs. Therefore, the amyloid plaques of prion diseases possess similar histochemical features to those found in Alzheimer's disease.Supported by Grant MT-3153 from the Medical Research Council of Canada, as well as research grants from the John Douglas French Foundation for Alzheimer's disease and the National Institutes of Health (NS22786, AG02132 and NS14069) and gifts from the R.J. Reynolds Industries, Sherman Fairchild Foundation, and Joseph and Stephaine Koret Foundation     

The metabolism of glycosaminoglycans is impaired in prion diseases

It is well established that the conversion of PrP(C) to PrP(Sc) is the key event in prion disease biology. In addition, several lines of evidence suggest that glycosaminoglycans (GAGs) and in particular heparan sulfate (HS) may play a role in the PrP(C) to PrP(Sc) conversion process. It has been proposed that PrP(Sc) accumulation in prion diseases may induce aberrant activation of lysosomal activity, which has been shown to result in neurodegeneration in a number of diseases, especially lysosomal storage disorders. Among such diseases, only the ones resulting from defects in GAGs degradation are accompanied by secretion of large amounts of GAG metabolites in urine. In this work, we show that GAGs are secreted in the urine of prion-infected animals and humans, and surprisingly, also in the urine of mice ablated for the PrP gene. We hypothesize that both the presence of PrP(Sc) or the absence of PrP(C) may alter the metabolism of GAGs.     

Neurological presentations of lysosomal diseases in adult patients

Lysosomal diseases represent a large group of genetic storage disorders characterized by a defect in the catabolism of complex molecules within the lysosome. Effective treatments are now possible for some of them given progresses in bone-marrow transplantation, enzyme replacement therapy and substrate reduction therapy. Neurologists and psychiatrists are concerned by these diseases because they can present in adolescence or adulthood with progressive neuropsychiatric signs. Here we focus on late-onset clinical forms which can be met in an adult neurology or psychiatric department. Lysosomal diseases were classified into 3 groups: (1) leukodystrophies (metachromatic leukodystrophy, Krabbe's disease and Salla's disease); (2) Neurodegenerative or psychiatric-like diseases (GM1 and GM2 gangliosidoses, Niemann Pick type C disease, sialidosis type I, ceroid-lipofuscinosis, mucopolysaccharidosis type III); (3) multisystemic diseases (Gaucher's disease, Fabry's disease, alpha and B mannosidosis, Niemann Pick disease type B, fucosidosis, Schindler/Kanzaki disease, and mucopolysaccharidosis type I and II. We propose a diagnostic approach guided by clinical examination, brain MRI, electrodiagnostic studies and abdominal echography.     

Chaperone therapy for molecular pathology in lysosomal diseases

In lysosomal diseases, enzyme deficiency is caused by misfolding of mutant enzyme protein with abnormal steric structure that is expressed by gene mutation. Chaperone therapy is a new molecular therapeutic approach primarily for lysosomal diseases. The misfolded mutant enzyme is digested rapidly or aggregated to induce endoplasmic reticulum stress. As a result, the catalytic activity is lost. The following sequence of events results in chaperone therapy to achieve correction of molecular pathology. An orally administered low molecular competitive inhibitor (chaperone) is absorbed into the bloodstream and reaches the target cells and tissues. The mutant enzyme is stabilized by the chaperone and subjected to normal enzyme protein folding (proteostasis). The first chaperone drug was developed for Fabry disease and is currently available in medical practice. At present three types of chaperones are available: competitive chaperone with enzyme inhibitory bioactivity (exogenous), non-competitive (or allosteric) chaperone without inhibitory bioactivity (exogenous), and molecular chaperone (heat shock protein; endogenous). The third endogenous chaperone would be directed to overexpression or activated by an exogenous low-molecular inducer. This new molecular therapeutic approach, utilizing the three types of chaperone, is expected to apply to a variety of diseases, genetic or non-genetic, and neurological or non-neurological, in addition to lysosomal diseases.     

Current strategies in the management of lysosomal storage diseases

Lysosomal storage diseases (LSDs) comprise a diverse group of over 40 clinically distinct inherited disorders. LSDs are progressive and may present at any age affecting any number of tissues and organ systems. They result from a genetic defect in cellular transport or metabolism of molecules within the lysosome. Treatment is directed toward symptomatic care of secondary complications for most of these diseases. For some individuals, hematopoietic stem cell transplantation or enzyme-replacement therapy can be effective. However, limitations in these therapies still exist. To date, there is no cure for any of the LSDs. Early diagnosis and treatment is essential for optimal treatment; this lends support to implementing mass newborn screening for LSDs.     

Recent developments in therapeutic approaches for lysosomal storage diseases

Genetic mutations that cause specific lysosomal protein deficiencies account for more than 45 Lysosomal Storage Diseases (LSDs), mostly pre-adult disorders which are associated with neurological symptoms and mental retardation. Interestingly, such diseases are often characterized by intracellular deposition and protein aggregation, events also found in age-related neurodegenerative diseases. During the past twenty years, different approaches have been introduced for the treatment of these disorders, several of which are now in routine clinical use or clinical trials. Among them, enzyme replacement therapy (ERT) represented a major progress. However, the usefulness of ERT is limited due to the fact that enzyme distribution is insufficient and treatment costs are very high. A further novel therapeutic option for LSDs is based on the use of small molecules, that can either inhibit a key enzyme which is responsible for substrate synthesis (substrate reduction) or act as a chaperone to increase the residual activity of the lysosomal enzyme (pharmacological chaperones). In addition, recently various gene therapy approaches have been developed, mostly based on adeno-associated and lentiviral vectors, and strategies based on stem cells administration are beginning their route. This review provides an update of the status of research on LSDs therapeutic approaches, including recent patents in the field.     

Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis

Paediatric neurodegenerative diseases are frequently caused by inborn errors in glycosphingolipid (GSL) catabolism and are collectively termed the glycosphingolipidoses. GSL catabolism occurs in the lysosome and a defect in an enzyme involved in GSL degradation leads to the lysosomal storage of its substrate(s). GSLs are abundantly expressed in the central nervous system (CNS) and the disorders frequently have a progressive neurodegenerative course. Our understanding of pathogenesis in these diseases is incomplete and currently few options exist for therapy. In this review we discuss how mouse models of these disorders are providing insights into pathogenesis and also leading to progress in evaluating experimental therapies.     

Abnormalities of developing white matter in lysosomal storage diseases.

Inborn metabolic errors causing lysosomal storage have well-recognized effects on neuronal function and morphology. In some classically "neuronal" storage diseases, however, neuroradiologic observations of infants have suggested a delay in central nervous system myelination based on persistently "immature" signal intensities monitored over time. This review summarizes reported neuropathologic evaluations of central white matter in infantile and juvenile patients and in corresponding animal models with lysosomal storage disorders. The observed neuropathology is examined in light of published studies of the biochemistry and microscopic anatomy of normal myelinogenesis. Finally, arguments are advanced that at least part of the deficiency of white matter is attributable to direct effects of the metabolic state on oligodendrocyte maturation and function, in addition to secondary effects on neurons and their axons.     

Chaperone therapy for lysosomal and non-lysosomal protein misfolding diseases

Chaperone therapy was introduced first as a new molecular therapeutic approach to lysosomal diseases. In a recent article, I reviewed the development of chaperone therapy mainly for lysosomal diseases. Then, more data have been collected particularly on non-lysosomal protein misfolding diseases. In this short review, I propose the concept of chaperone therapy to be classified into two different therapeutic approaches, for pH-dependent lysosomal, and pH-independent non-lysosomal protein misfolding diseases. The concept of lysosomal chaperone therapy is well established, but the non-lysosomal chaperone therapy is heterogeneous and to be investigated further for various individual diseases. As a whole, these two-types of new molecular therapeutic approaches will make an impact on the treatment of a wide range of pathological conditions caused by protein misfolding, not necessarily lysosomal but also many non-lysosomal diseases caused by gene mutations, metabolic diseases, malignancy, infectious diseases, and aging. The concept will open a completely new aspect of protein therapy in future.     

Ultrastructural pathology of dermal axons and Schwann cells in lysosomal diseases

Summary Skin tissue specimens, obtained from 60 patients afflicted with a diverse range of lysosomal disorders revealed two groups of lesions within dermal axons, largely unmyelinated ones, particularly within axonal terminals: (1) non-specific mitochondria and dense bodies often enlarging the axonal terminal; and (2) disease-specific lysosomal residual bodies, the latter less frequent depending on the incidence and type of lysosomal disorders, i.e., largely only seen in GM₂-gangliosidosis due to hexosaminidase A deficiency and mucolipidosis IV, while the spectrum of lysosomal residual bodies in Schwann cells appeared more variegated, especially due to the occurrence of vacuolar lysosomal residual bodies which were never seen within axons. The most frequent location of abnormal intraaxonal constituents in terminal axons indicates a functionally and morphologically impaired retrograde axonal transport but provides no further evidence as to whether the respective parent nerve cell body has also accumulated lysosomal residual bodies. When studying biopsied skin specimens for diagnosis, axonal terminals beneath the epidermis, about sweat glands, and among smooth muscle cells, ought to be incorporated into a comprehensive electron microscopic examination.This paper was, in part, presented at the Annual Meeting of the Deutsche Gesellschaft für neuropathologie und Neuroanatomie, Mainz, October 1986, and represents part of a medical thesis by S. Walter to be submitted to the Fachbereich Medizin der Johannes-Gutenberg-Universität Mainz     

Phosphomannosyl receptors of lysosomal enzymes of skeletal muscle in neuromuscular diseases

The phosphomannosyl receptor system is responsible for both the receptor-mediated endocytosis and the intracellular transport of lysosomal enzymes. In the present study this receptor system was examined in affected muscles of patients with various neuromuscular diseases. The total activity of beta-N-acetyl-glucosaminidase, a marker enzyme of lysosomal hydrolases, was significantly elevated in the patients with myopathies (polymyositis and muscular dystrophies) but only slightly increased in those with neurogenic muscle atrophies (amyotrophic lateral sclerosis, polyneuropathy or other neurogenic muscle disease). The increase was most prominent in the group of polymyositis. The content of phosphomannosyl receptors was increased in the patients with myogenic muscle disease but not in those with neurogenic disease. The receptor binding of lysosomal enzymes was saturable and inhibited with mannose 6-phosphate showing the typical characteristics of phosphomannosyl receptors. The characteristics of the receptors were very similar both to control and to diseased muscle samples. When surveying all the material, the content of phosphomannosyl receptors correlated highly significantly with the muscular activity of beta-N-acetylglucosaminidase, muscle atrophy index, and serum creatine kinase activity.     

Insights into the diagnosis and treatment of lysosomal storage diseases

Lysosomal storage diseases (LSDs) are a group of genetic disorders that result from defective lysosomal metabolism or export of naturally occurring compounds. Signs and symptoms are variable both within and between disorders depending on the location and extent of storage. Many patients develop neurologic symptoms that become obvious from the newborn period to adulthood. Diagnosis of suspected patients can usually be made by measuring the activity of an enzyme or concentration of a metabolite in easily obtained tissue samples. Based on the considerable diagnostic experience of our laboratory, we aid the physician in selecting the appropriate tests to perform. Hematopoietic stem cell transplantation and enzyme replacement therapy are already available or in clinical trials for a number of LSDs. Early diagnosis is critical, especially since those patients who are treated before significant symptoms arise have the best chance for a positive outcome.     

Molecular pathologies of and enzyme replacement therapies for lysosomal diseases

Lysosomal diseases comprise a group of inherited disorders resulting from defects of lysosomal enzymes and their cofactors, and in many of them the nervous system is affected. Recently, enzyme replacement therapy with recombinant lysosomal enzymes has been clinically available for several lysosomal diseases. Such enzyme replacement therapies can improve non-neurological disorders but is not effective for neurological ones. In this review, we discuss the molecular pathologies of lysosomal diseases from the protein structural aspect, current enzyme replacement therapies, and attempts to develop enzyme replacement therapies effective for lysosomal diseases associated with neurological disorders, i.e., production of enzymes, brain-specific delivery and incorporation of lysosomal enzymes into cells.     

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal‐recessive or X‐linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in accumulation of nondegraded substrates. Although lysosomal storage disorders are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany many lysosomal storage disorders. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between lysosomal storage disorders and adult‐onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher's disease and are among the most common and potent risk factors for PD. However, recently, many additional lysosomal storage disorder genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of PD and guide development of new therapeutic strategies. We systematically review the emerging genetic links between lysosomal storage disorders and PD. © 2019 International Parkinson and Movement Disorder Society