Introduction: The key role of lysosome in cellular processes has received more and more attention. Need to understand the balanced interactions between the acidic hydrolase , lysosomal membrane proteins and cytoplasmic proteins. Lysosomal storage diseases (LSDs) are characterized by disturbances in this network and lysosomal accumulation of substrates, usually only in certain cell types, and require extra attention once they appear.
Despite our increased understanding of these disorders and established treatments, many aspects of the molecular pathology of LSD remain obscure. This review aims to discuss how lysosomal storage affects lysosome-related functions such as membrane repair, autophagy, exocytosis, lipid homeostasis, signaling cascades, and cell viability. Morphological correction of lysosomal storage and reversal of pathological and biochemical outcomes is the key to therapy. Since different LSDs have different molecular causes, therapies need to be tailored.
1. What kind of disease is lysosomal storage disease? At present, experts believe that the main cause of this disease is closely related to the abnormal production of lysosomes in the body. The membrane transporter or the gene mutation of the transporter may cause LSD in humans or animals. The incidence of LSD is 1 in 7000 live births and varies according to the lipid storage disorders involved ( sphingolipids , gangliosides , leukocytes dystrophies), mucopolysaccharides , sugars Protein storage disorder, mucolipase and cystinopathy. LSD is inherited in an autosomal recessive or some X-linked manner. Typical clinical symptoms include hepatosplenomegaly , lung and heart problems, skeletal abnormalities, dementia , deafness , blindness and motor problems. Two-thirds of LSDs are neurologically functional.
2, etiology
Lysosomal proteins are synthesized in the endoplasmic reticulum and transported to the lysosomal system through the secretory pathway. Several receptors have been characterized that perform lysosomal protein trafficking after Golgi . Some of them identify their living proteins based on specific amino acid signatures, others based on specific glycan modifications found only on lysosomal proteins. Almost all receptors for lysosomal biogenesis are under the transcriptional control of transcription factor EB (TFEB), a master regulator of the lysosomal system.
TFEB coordinates the expression of lysosomal hydrolases, lysosomal membrane proteins and autophagy proteins in response to pathways that sense cellular nutritional status under lysosomal stress and other stimulatory conditions. TFEB is activated in lysosomal storage diseases, but surprisingly its function is limited in some late-onset neurodegenerative storage diseases (such as ) due to certain deleterious interactions that limit TFEB expression or activation. Impaired in Alzheimer's disease and Parkinson's disease ).
Thus, disruptive TFEB function may play a role in the pathogenesis of these diseases. Multiple studies in animal models of degenerative storage diseases have demonstrated that exogenous expression of TFEB and pharmacological activation of endogenous TFEB attenuates the disease phenotype.
Second, lysosomal storage diseases are divided into 9 types, and the specific causes of different types are different. Basically, they are caused by the gene .
1, Gaucher's disease (GD)
This is the most common LSD, is caused by the mutation in the GBA gene ( locus 1q21), which encodes the (hemolytic) glucosyl ceramide degrading enzyme β-glucocerebrosidase (EC 3.2.1.45). Type I GD is the chronic, non-neurological and most common form of the disease, characterized by organ enlargement, bone involvement, and cytopenias.Types II and III have earlier onset and progressive brain involvement.
2, Fabry disease (FD)
X-linked glycosphingolipidemia caused by deficiency of lysosomal alpha-galactosidase A (EC 3.2.1.22) encoded by the GLA gene (Xq22.1), resulting in ballooning Lysosomal accumulation of glycosylceramide (Gb3). FD is a multisystem pathology characterized by specific renal, cardiovascular and neurological manifestations.
3, Krabbe disease (KD)
is caused by a mutation in the GALC gene (locus 14q31.3) encoding galactocerebrosidase (EC 3.2.1.46). KD, also known as spherocytic leukodystrophy, causes the accumulation of undegraded galactolipids, including psychotropic drugs. This leads to progressive demyelination of cells in the nervous system, and ultimately a decline in cognitive and motor function.
4, GM1 and GM2 gangliosidases,
These are the acid enzymes β-galactosidase [EC 3.2.1.23 encoded by GLB1(3p22)] and β-hexosaminidase [encoded by HEXA(15q23), respectively] and HEXB (5q13)-encoded EC 3.2.1.52] deficiency and is characterized by accumulation of gangliosides. GM1 and GM2 gangliosidases exhibit very severe neurological symptoms. GM2 gangliosidase is also known as Tay-Sachs or Sandohoff disease, depending on whether the A or B subunits of hexosaminidase are deficient.
5, Niemann–Pick type C (NPC)
is caused by a deficiency in the lysosomal cholesterol export machinery resulting from mutations in the NPC1 (18q11.2) and NPC2 (14q24.3) genes. NPCs lead to the accumulation of cholesterol and sphingolipids within the lysosomes, leading to severe neurological and visceral pathology.
6, Pompe disease
Also known as type II glycogen storage disease, glycogen caused by deficiency of lysosomal alpha-glucosidase (EC3.2.1.3) encoded by GAA gene (17q25.3) Caused by accumulation. Patients are unable to degrade glycogen, which is stored in lysosomes, especially in muscle cells, resulting in cardiac and respiratory failure .
7, Neuronal steroid lipofucose (NCL)
Fourteen genetically heterogeneous diseases caused by mutations in genes encoding lysosomal soluble and membrane proteins and one ER protein. NCL co-accumulates an autofluorescent pigment, the lipid lipofuscin, leading to neurodegeneration and blindness.
8, mucopolysaccharidase (MPS)
MPS is divided into seven subtypes and is caused by a deficiency of lysosomal enzymes necessary for glycosaminoglycan (GAG) degradation. GAG storage affects bone, skeletal tissue, cartilage and connective tissue , as well as the peripheral and central nervous systems.
9, mucolipases (MLs)
These pathologies are clinically and biochemically characterized by MPS and sphingolipids, characterized by the accumulation of glycoproteins and glycolipids . ML type I (or sialic acidosis) is caused by deficiency of sialidase [EC 3.2.1.18, encoded by NEU1 (6p21.33)]. Types II and III ML are caused by deficiency of N-acetylglucosamine phosphoramidotransferase [EC 2.7.8.17, encoded by GNPTAB (12q23.2)], the enzyme responsible for making mannose residues in newly synthesized glycoproteins base phosphorylation. ML type IV is caused by mutations in the MCOLN1 gene (locus 19p13.2-13.3), which encodes a lysosomal membrane cation channel involved in Ca signaling.
Conclusion: Despite progress in understanding lysosomal compartments and different diseases caused by mutations or deficiencies in lysosomal proteins, we are still unable to fully explain individual pathologies.Since lysosomal function is closely related to autophagy and phagocytosis, a better understanding of the abnormalities of these pathways in LSD cells is also required. Furthermore, inappropriate storage caused by the deficiency of acid hydrolases or specific transporters is only one aspect of disease pathology, and the exact molecular mechanisms of LSD can only be fully understood when we consider that all (altered) cellular functions are affected.
Subtle changes in lysosomal compartments may not only explain some of the changes in common human diseases, but are also associated with physiological processes such as senescence, immune function, and regulation of cell death and proliferation. In terms of available and future treatments, we will need to be aware that many interventions may only be partially effective, and when targeting lysosomal diseases, combination therapies and suitable therapeutic windows may have to be identified to circumvent any adverse side effects.
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