The expression of the gene asebia in the laboratory mouse: I. Epidermis and dermis

SUMMARYMice homozygous for the asebia mutation (ab/ab), which have defective sebaceous glands, display abnormalities in several other aspects of the integument. Histological sections showed that hyperplasia of the cellular layers and the stratum corneum of the epidermis is apparent at birth and increases markedly with age. Enlarged intercellular spaces are also noted in the epidermis. The thicker dermal layer of the asebic mice is characterized by increased vascularity, increased cellularity and the abnormal morphology of a large proportion of the ‘fibroblast’ population. Electron microscopy demonstrated the many abnormalities in the dermal fibroblasts as well as large amounts of cellular debris in the surrounding matrix. Collagen and elastin show alterations at the light microscopic and ultrastructural levels. Many features of the asebic dermis resemble those found with mild inflammation and with the lysosomal storage diseases. Changes in the dermis of asebic foetuses were noted prior to epidermal alterations and may mediate the latter.

Download Full-text

Autophagy promotes cell survival by maintaining NAD(H) levels

10.21203/rs.3.rs-659023/v1 ◽

2021 ◽

Author(s):

Lucia Sedlackova ◽

Tetsushi Kataura ◽

Elena Seranova ◽

Congxin Sun ◽

Elsje Otten ◽

...

Keyword(s):

Cell Survival ◽

Lysosomal Storage Diseases ◽

Lysosomal Storage ◽

Cellular Functions ◽

Cellular Survival ◽

Tissue Degeneration ◽

Therapeutic Benefits ◽

Age Related ◽

Membrane Depolarisation ◽

The Many

Abstract Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components1. As a recycling process, autophagy is also important for the maintenance of cellular metabolites to aid metabolic homeostasis2. Loss of autophagy in animal models or malfunction of this process in a number of age-related human pathologies, including neurodegenerative and lysosomal storage diseases, contributes to tissue degeneration3-9. However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD+/NADH) levels, which are critical for cellular survival. In respiring cells, loss of autophagy caused hyperactivation of PARP and Sirtuin families of NADases. Uncontrolled depletion of NAD(H) pool by these enzymes resulted in mitochondrial membrane depolarisation and cell death. Supplementation with NAD(H) precursors improved cell viability in autophagy-deficient models including human pluripotent stem cell-derived neurons with autophagy deficiency or patient-derived neurons with autophagy dysfunction. Our study provides a mechanistic link between autophagy and NAD(H) metabolism, and suggests that boosting NAD(H) levels may have therapeutic benefits in human diseases associated with autophagy dysfunction.

Download Full-text

Electron Microscopy in the diagnosis of lysosomal storage diseases

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100156316 ◽

1989 ◽

Vol 47 ◽

pp. 866-867

Author(s):

Carole Vogler ◽

Harvey S. Rosenberg

Keyword(s):

Electron Microscopy ◽

Lysosomal Enzyme ◽

Rectal Mucosa ◽

Lysosomal Storage Diseases ◽

Cell Types ◽

Lysosomal Storage ◽

Storage Material ◽

Ultrastructural Examination ◽

Blood Leukocytes ◽

Storage Diseases

Diagnostic procedures for evaluation of patients with lysosomal storage diseases (LSD) seek to identify a deficiency of a responsible lysosomal enzyme or accumulation of a substance that requires the missing enzyme for degradation. Most patients with LSD have progressive neurological degeneration and may have a variety of musculoskeletal and visceral abnormalities. In the LSD, the abnormally diminished lysosomal enzyme results in accumulation of unmetabolized catabolites in distended lysosomes. Because of the subcellular morphology and size of lysosomes, electron microscopy is an ideal tool to study tissue from patients with suspected LSD. In patients with LSD all cells lack the specific lysosomal enzyme but the distribution of storage material is dependent on the extent of catabolism of the substrate in each cell type under normal circumstances. Lysosmal storages diseases affect many cell types and tissues. Storage material though does not accumulate in all tissues and cell types and may be different biochemically and morphologically in different tissues.Conjunctiva, skin, rectal mucosa and peripheral blood leukocytes may show ultrastructural evidence of lysosomal storage even in the absence of clinical findings and thus any of these tissues can be used for ultrastructural examination in the diagnostic evaluation of patients with suspected LSD. Biopsy of skin and conjunctiva are easily obtained and provide multiple cell types including endothelium, epithelium, fibroblasts and nerves for ultrastructural study. Fibroblasts from skin and conjunctiva can also be utilized for the initiation of tissue cultures for chemical assays. Brain biopsy has been largely replaced by biopsy of more readily obtained tissue and by biochemical assays. Such assays though may give equivical or nondiagnostic results and in some lysosomal storage diseases an enzyme defect has not yet been identified and diagnoses can be made only by ultrastructural examination.

Download Full-text

Substrate reduction therapy for lysosomal storage diseases

Acta Paediatrica ◽

10.1080/08035320510028157 ◽

2005 ◽

Vol 94 (0) ◽

pp. 69-75 ◽

Cited By ~ 34

Author(s):

T Cox

Keyword(s):

Lysosomal Storage Diseases ◽

Substrate Reduction Therapy ◽

Lysosomal Storage ◽

Storage Diseases ◽

Substrate Reduction

Download Full-text

Bone Marrow Transplantation in the Treatment of Lysosomal Storage Diseases

Inborn Metabolic Diseases ◽

10.1007/978-3-662-02613-7_52 ◽

1990 ◽

pp. 659-670 ◽

Cited By ~ 5

Author(s):

P. M. Hoogerbrugge ◽

J. M. J. J. Vossen

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Lysosomal Storage Diseases ◽

Lysosomal Storage ◽

Storage Diseases

Download Full-text

The role of surfactant and distal lung dysfunction in the pathology of lysosomal storage diseases

Current Opinion in Physiology ◽

10.1016/j.cophys.2021.100467 ◽

2021 ◽

pp. 100467

Author(s):

Tamara L Paget ◽

Emma J Parkinson-Lawrence ◽

Sandra Orgeig

Keyword(s):

Lysosomal Storage Diseases ◽

Lysosomal Storage ◽

Storage Diseases ◽

Lung Dysfunction ◽

Distal Lung

Download Full-text

Sphingolipid lysosomal storage diseases: from bench to bedside

Lipids in Health and Disease ◽

10.1186/s12944-021-01466-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Muna Abed Rabbo ◽

Yara Khodour ◽

Laurie S. Kaguni ◽

Johnny Stiban

Keyword(s):

Basic Research ◽

Lysosomal Storage Diseases ◽

Therapeutic Strategies ◽

Clinical Applications ◽

Late Nineteenth Century ◽

Lysosomal Storage ◽

Storage Diseases ◽

The Past ◽

Health And Disease ◽

General Aspects

AbstractJohann Ludwig Wilhelm Thudicum described sphingolipids (SLs) in the late nineteenth century, but it was only in the past fifty years that SL research surged in importance and applicability. Currently, sphingolipids and their metabolism are hotly debated topics in various biochemical fields. Similar to other macromolecular reactions, SL metabolism has important implications in health and disease in most cells. A plethora of SL-related genetic ailments has been described. Defects in SL catabolism can cause the accumulation of SLs, leading to many types of lysosomal storage diseases (LSDs) collectively called sphingolipidoses. These diseases mainly impact the neuronal and immune systems, but other systems can be affected as well. This review aims to present a comprehensive, up-to-date picture of the rapidly growing field of sphingolipid LSDs, their etiology, pathology, and potential therapeutic strategies. We first describe LSDs biochemically and briefly discuss their catabolism, followed by general aspects of the major diseases such as Gaucher, Krabbe, Fabry, and Farber among others. We conclude with an overview of the available and potential future therapies for many of the diseases. We strive to present the most important and recent findings from basic research and clinical applications, and to provide a valuable source for understanding these disorders.

Download Full-text