Neuronal-specific impairment of heparan sulfate degradation in Drosophila reveals pathogenic mechanisms for Mucopolysaccharidosis type IIIA

Webber, Dani L.; Choo, Amanda; Hewson, Laura J; Trim, Paul J.; Snel, Marten F.; Hopwood, John J.; Richards, Robert I.; Hemsley, Kim M.; O’Keefe, Louise V.

doi:10.1016/j.expneurol.2018.01.020

Cited by 17 publications

(41 citation statements)

References 76 publications

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“…Interestingly, in a neuron-specific Drosophila model of MPS IIIA disease, blockage of apoptotic pathways did not improve behavioral phenotype. That aligns with the idea that cell death is not the only pathological cause of clinical decline [60]. Nevertheless, morphological changes can still hold value as markers of disease progression.…”

Section: Neuronal Death In Mps IIIsupporting

confidence: 76%

“…Further evidence that the blockage of autophagy contributes to the pathology of Sanfilippo disease has been obtained using the Sgsh knockdown Drosophila model of MPS IIIA showing lysosomal storage of heparan sulfate in neurons and reduced ability to climb, suggesting neurological impairment [60]. It has been demonstrated that knockdown of Atg18 and Atg1, both essential components of the autophagic machinery, in these MPS IIIA flies led to worse performance in the climbing assay [60].…”

Section: Autophagic Defects and Accumulation Of Protein Aggregatesmentioning

confidence: 99%

“…MPS III in canine and caprine models manifests mainly by ataxia and gait abnormalities [55][56][57]59], whereas human patients develop motor deficits due to degeneration of the CNS much later in the disease. A specific model for studying the neuropathology of MPS IIIA was generated in Drosophila and showed a knockdown of SGSH limited to neurons [60]. In addition, a NAGLU heterozygous model was recently developed in large white boars and presented with common symptoms found in MPS IIIB patients, such as slow growth, early death, somatic changes and cerebral abnormalities [61].…”

Section: Animal Models Of Mps IIImentioning

confidence: 99%

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Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area.

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Section: Neuronal Death In Mps IIIsupporting

confidence: 76%

Section: Autophagic Defects and Accumulation Of Protein Aggregatesmentioning

confidence: 99%

Section: Animal Models Of Mps IIImentioning

confidence: 99%

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Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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“…Autophagy was shown to be also impaired in several other MPS animal models, including MPS II [51], MPS IIIC [52], MPS VI [53], and MPS VII [54]. Changes in expression of autophagy-related genes, coding for Atg1 and Atg18 proteins, were recently reported in MPS IIIA [50]. Another intriguing link between autophagy impairment and MPS has been discovered recently [55].…”

Section: Abnormal Autophagymentioning

confidence: 94%

“…These MPS IIIA flies showed reduced ability to climb, indicating neurological impairment. Knockdown of Atg18 and Atg1, both essential components of the autophagic pathway, resulted in further worsening of performance in the climbing assay [50], suggesting a role of autophagy in the pathophysiology of the disease. Autophagy was shown to be also impaired in several other MPS animal models, including MPS II [51], MPS IIIC [52], MPS VI [53], and MPS VII [54].…”

Section: Abnormal Autophagymentioning

confidence: 99%

Pathogenesis of Mucopolysaccharidoses, an Update

Fecarotta

Tarallo

Damiano

et al. 2020

IJMS

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The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders.

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Changes in cellular processes occurring in mucopolysaccharidoses as underestimated pathomechanisms of these diseases

Gaffke

Pierzynowska

Podlacha

et al. 2020

Cell Biology International

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Mucopolysaccharidoses (MPS) are a group of genetic disorders belonging to lysosomal storage diseases. They are caused by genetic defects leading to a lack or severe deficiency of activity of one of lysosomal hydrolases involved in degradation of glycosaminoglycans (GAGs). Partially degraded GAGs accumulate in lysosomes, which results in dysfunctions of cells, tissues, and organs. Until recently, it was assumed that GAG accumulation in cells is the major, if not the only, mechanism of pathogenesis in MPS, as GAGs may be a physical ballast for lysosomes causing inefficiency of cells due to a large amount of a stored material. However, recent reports suggest that in MPS cells there are changes in many different processes, which might be even more important for pathogenesis than lysosomal accumulation of GAGs per se. Moreover, there are many recently published results indicating that lysosomes not only are responsible for degradation of various macromolecules, but also play crucial roles in the regulation of cellular metabolism. Therefore, it appears plausible that previous failures in treatment of MPS (i.e., possibility to correct only some symptoms and slowing down of the disease rather than fully effective management of MPS) might be caused by underestimation of changes in cellular processes and concentration solely on decreasing GAG levels in cells.

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Neuronal-specific impairment of heparan sulfate degradation in Drosophila reveals pathogenic mechanisms for Mucopolysaccharidosis type IIIA

Cited by 17 publications

References 76 publications

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Pathogenesis of Mucopolysaccharidoses, an Update

Changes in cellular processes occurring in mucopolysaccharidoses as underestimated pathomechanisms of these diseases

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