Gaucher disease: pathological mechanisms and modern management

Jmoudiak, Marina; Futerman, Anthony H.

doi:10.1111/j.1365-2141.2004.05351.x

Cited by 251 publications

(195 citation statements)

References 102 publications

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“…The breakdown products resulting from the proteolysis may also be atypical and pathogenic; there is evidence that cytoplasmic cathepsin D produces a tau protein fragment comparable to that thought to 'seed' the formation of neurofibrillary tangles Lynch, 1996, 1998), while inhibitors of the enzyme block the development of phosphorylated tau deposits (Bi et al, 2000). Third, metabolism within lysosomes generates products necessary for proper functioning of the endoplasmic reticulum, the loss of which can impair calcium buffering (Jmoudiak and Futerman, 2005). This would have a diverse array of effects including activation of the calcium-sensitive protease calpain (Fig.…”

Section: Relationship Of Plasticity Deficits To Generalized Brain Agingmentioning

confidence: 99%

Synaptic plasticity in early aging

Lynch

Rex

Gall

2006

Ageing Research Reviews

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Studies of how aging affects brain plasticity have largely focused on old animals. However, deterioration of memory begins well in advance of old age in animals, including humans; the present review is concerned with the possibility that changes in synaptic plasticity, as found in the long-term potentiation (LTP) effect, are responsible for this. Recent results indicate that impairments to LTP are in fact present by early middle age in rats but only in certain dendritic domains. The search for the origins of these early aging effects necessarily involves ongoing analyses of how LTP is induced, expressed, and stabilized. Such work points to the conclusion that cellular mechanisms responsible for LTP are redundant and modulated both positively and negatively by factors released during induction of potentiation. Tests for causes of the localized failure of LTP during early aging suggest that the problem lies in excessive activity of a negative modulator. The view of LTP as having redundant and modulated substrates also suggests a number of approaches for reversing age-related losses. Particular attention will be given to the idea that induction of brain-derived neurotrophic factor, an extremely potent positive modulator, can be used to provide long periods of normal plasticity with very brief pharmacological interventions. The review concludes with a consideration of how the selective, regional deficits in LTP found in early middle age might be related to the global phenomenon of brain aging. #

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Section: Relationship Of Plasticity Deficits To Generalized Brain Agingmentioning

confidence: 99%

Synaptic plasticity in early aging

Lynch

Rex

Gall

2006

Ageing Research Reviews

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“…Similarly, in the neuronal models of GD, it was shown that GlcCer directly activated phospholipid synthesis by activation of CTP:phosphocholine cytidylyltransferase (CCT), which was shifted from cytosol to the endoplasmic reticulum (Bodennec et al 2002;Korkotian et al 1999;Pelled et al 2005). All these phenomena could be explained by the transfer of the uncleaved lysosomal GlcCer into the neuronal endoplasmic reticulum (Bodennec et al 2002;Jmoudiak and Futerman 2005). The role of GlcSph in neuronal degeneration is mentioned below.…”

Section: Glucosylceramide Transfermentioning

confidence: 99%

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Elleder

2006

J of Inher Metab Disea

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SummaryGaucher disease (GD), deficiency of acid glucosylceramidase (GlcCer‐ase) is characterized by deficient degradation of beta‐glucosylceramide (GlcCer). It is well known that, in GD, the lysosomal accumulation of uncleaved GlcCer is limited to macrophages, which are gradually converted to storage cells with well known cytology—Gaucher cells (GCs). On the basis of previous studies of the disorder and of a comparison with other lysosomal enzymopathies affecting degradation of the GlcCer‐based glycosphingolipid series, it is hypothesized that in other cell types (i.e. non‐macrophage cells) the uncleaved GlcCer, in GlcCer‐ase deficiency, is transferred to other cell compartments, where it may be processed and even accumulated to various degrees. The consequence of the abnormal extralysosomal load may differ according to the cell type and compartment targeted and may be influenced by genetically determined factors, by a number of acquired conditions, including the current metabolic situation. The sequelae of the uncleaved GlcCer extralysosomal transfer may range from probably innocent or positive stimulatory, to the much more serious, in which it interferes with a variety of cell functions, and in extreme cases, can lead to cell death. This alternative processing of uncleaved GlcCer may help to explain tissue alterations seen in GD that have, so far, resisted explanation based simply on the presence of GCs. Paralysosomal alternative processing may thus go a long way towards filling a long‐standing gap in the understanding of the molecular pathology of the disorder. The impact of this alternative process will most likely be inversely proportional to the level of residual GlcCer‐ase activity. Lysosomal sequestration of GlcCer in these cells is either absent or in those exceptional cases where it does occur, it is exceptional and rudimentary. It is suggested that paralysosomal alternative processing of uncleaved GlcCer is the main target for enzyme replacement therapy. The mechanism responsible for GlcCer transfer remains to be elucidated. It may also help in explaining the so far unclear origin of glucosylsphingosine (GlcSph) and define the mutual relation between these two processes.

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“…The deficient activity of this enzyme results in the accumulation of glucosylceramide (GlcCer) within the lysosomes. Type I (GD1) is the most common form of GD and may imply a large variety of symptoms, ranging from completely asymptomatic to child-onset forms (Beutler and Grabowski 2001;Jmoudiak and Futerman 2005).…”

Section: Introductionmentioning

confidence: 99%

Did the Temporary Shortage in Supply of Imiglucerase Have Clinical Consequences? Retrospective Observational Study on 34 Italian Gaucher Type I Patients

et al. 2012

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Background. Enzyme Replacement Therapy (ERT) is the standard of care in Gaucher disease. The effects of withdrawal or reduced doses are debated, thus a retrospective cohort study was conducted to investigate clinical and laboratory differences in 34 Gaucher type 1 patients experiencing an ERT dosage reduction after the forced temporary imiglucerase shortage in 2009.Methods. Haemoglobin concentration, leukocytes and platelets counts, and chitotriosidase activity were assessed at baseline and after 6 and 12 months (t0, t6, t12), while bone pain, energy, work or school performance, concentration, memory and social life every 3 months.

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Gaucher disease: pathological mechanisms and modern management

Cited by 251 publications

References 102 publications

Synaptic plasticity in early aging

Synaptic plasticity in early aging

Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Did the Temporary Shortage in Supply of Imiglucerase Have Clinical Consequences? Retrospective Observational Study on 34 Italian Gaucher Type I Patients

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