Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease

Farfel-Becker, Tamar; Vitner, Einat B.; Pressey, Sarah N.R.; Eilam, Raya; Cooper, Jonathan D.; Futerman, Anthony H.

doi:10.1093/hmg/ddr019

Cited by 96 publications

(95 citation statements)

References 31 publications

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“…Indeed, the thalamus consistently appears to be an important and early disease focus in many different LSDs, as is revealed by T2 imaging of these patients (43), and pronounced thalamic pathology has been shown in mouse models of all forms of NCL (reviewed in ref. 44) and all other LSDs we have examined (e.g., 45,46). As such, it will be important to direct therapies to this brain region, and this may be key for improving therapeutic outcome further.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1 −/− ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1 −/− mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1 −/− mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.infantile Batten disease | adeno-associated virus | spinal cord | brain | combination therapy

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Section: Discussionmentioning

confidence: 99%

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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“…Measurements of GlcCer and GlcSph in brain samples from patients with GD reveal that GlcSph is greatly elevated in neuronopathic GD, with the highest levels seen in Type 2 [19]. Recent work by Futerman and colleagues using a mouse model of neuronopathic GD found that the continued accumulation of GlcCer reaches a critical threshold that triggers a rapid cascade leading to neuroinflammation and neurodegeneration in certain brain regions [20,21]. …”

Section: Pathophysiologymentioning

confidence: 99%

The clinical management of type 2 Gaucher disease

Weiss

Gonzalez

Lopez

et al. 2015

Molecular Genetics and Metabolism

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Gaucher disease, the inherited deficiency of the enzyme glucocerebrosidase, is the most common of the lysosomal storage disorders. Type 2 Gaucher disease, the most severe and progressive form, manifests either prenatally or in the first months of life, followed by death within the first years of life. The rarity of the many lysosomal storage disorders makes their diagnosis a challenge, especially in the newborn period when the focus is often on more prevalent illnesses. Thus, a heightened awareness of the presentation of these rare diseases is necessary to ensure their timely consideration. This review, designed to serve as a guide to physicians treating newborns and infants with Gaucher disease, discusses the presenting manifestations of Type 2 Gaucher disease, the diagnostic work-up, associated genotypes and suggestions for management. We also address the ethical concerns that may arise with this progressive and lethal disorder, since currently available treatments may prolong life, but do not impact the neurological manifestations of the disease.

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“…Neuroinflammation is implicated in the progressive nature of several neurodegenerative diseases and is described in almost all LSDs with neurological involvement (21)(22)(23)(24)(25)(26)(27). However, it is still unclear whether macrophage and astrocyte activation in LSDs is triggered by their intracellular storage or represents a response to neuronal damage.…”

Section: Lysosomal Storage In Neurons Elicits Neuroinflammation In Msdmentioning

confidence: 99%

Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder

Malta

Fryer

Settembre

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

103

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The role of astrocytes in neurodegenerative processes is increasingly appreciated. Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene. Using Cre/Lox mouse models, we found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of autophagic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo. Furthermore, in an ex vivo coculture assay, we observed that Sumf1 −/− astrocytes failed to support the survival and function of wild-type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration. Compared with the astrocyte-specific deletion of Sumf1, the concomitant removal of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioral analysis of mice with astrocyte-specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed us to link a subset of neurological manifestations of MSD to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in MSD and that modulation of astrocyte function may impact disease course.ultiple sulfatase deficiency (MSD) is a lysosomal storage disorder (LSD) caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene that results in aberrant posttranslation modification of sulfatases (1). Sulfatases are a family of enzymes required for the turnover and degradation of sulfated compounds. Eight known metabolic disorders are caused by the deficiency of individual sulfatase activities. Six are LSDs (five mucopolysaccharidoses and metachromatic leukodystrophy); the remaining two disorders are caused by deficiency of nonlysosomal sulfatases. The impaired activity of all sulfatases in MSD is responsible for a very severe phenotype that combines all the clinical symptoms found in each individual sulfatase deficiency (2). As in many other LSDs, progressive and severe neurodegeneration is a prominent feature and is the most difficult challenge for therapy (3). Previous studies identified impaired autophagy in neurons as a crucial component in the pathogenic mechanisms leading to neurodegeneration in MSD as well as in other LSDs (4,5). This lysosomal accumulation of undegraded substrates results in defective degradation of autophagosomes and causes a block of the autophagy pathway leading to an accumulation of ubiquitinated proteins, dysfunctional mitochondria, and neurodegeneration. To date, research has focused on neurons, but the contribution of nonneuronal cells to the neuropathology of MSD has remained largely unexplored.Astrocytes play crucial roles in adult CNS homeostasis (6), including synaptic glutamate uptake (7), maintenance of extracellular potassium (8), and nutrient support for neuro...

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Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease

Cited by 96 publications

References 31 publications

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Synergistic effects of treating the spinal cord and brain in CLN1 disease

The clinical management of type 2 Gaucher disease

Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder

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