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Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice.

ABSTRACT: Gaucher disease, a prevalent lysosomal storage disease (LSD), is caused by insufficient activity of acid ?-glucosidase (GCase) and the resultant glucosylceramide (GC)/glucosylsphingosine (GS) accumulation in visceral organs (Type 1) and the central nervous system (Types 2 and 3). Recent clinical and genetic studies implicate a pathogenic link between Gaucher and neurodegenerative diseases. The aggregation and inclusion bodies of ?-synuclein with ubiquitin are present in the brains of Gaucher disease patients and mouse models. Indirect evidence of ?-amyloid pathology promoting ?-synuclein fibrillation supports these pathogenic proteins as a common feature in neurodegenerative diseases. Here, multiple proteins are implicated in the pathogenesis of chronic neuronopathic Gaucher disease (nGD). Immunohistochemical and biochemical analyses showed significant amounts of ?-amyloid and amyloid precursor protein (APP) aggregates in the cortex, hippocampus, stratum and substantia nigra of the nGD mice. APP aggregates were in neuronal cells and colocalized with ?-synuclein signals. A majority of APP co-localized with the mitochondrial markers TOM40 and Cox IV; a small portion co-localized with the autophagy proteins, P62/LC3, and the lysosomal marker, LAMP1. In cultured wild-type brain cortical neural cells, the GCase-irreversible inhibitor, conduritol B epoxide (CBE), reproduced the APP/?-synuclein aggregation and the accumulation of GC/GS. Ultrastructural studies showed numerous larger-sized and electron-dense mitochondria in nGD cerebral cortical neural cells. Significant reductions of mitochondrial adenosine triphosphate production and oxygen consumption (28-40%) were detected in nGD brains and in CBE-treated neural cells. These studies implicate defective GCase function and GC/GS accumulation as risk factors for mitochondrial dysfunction and the multi-proteinopathies (?-synuclein-, APP- and A?-aggregates) in nGD.

SUBMITTER: Xu YH

PROVIDER: S-EPMC4082362 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice.

Xu You-hai YH Xu Kui K Sun Ying Y Liou Benjamin B Quinn Brian B Li Rong-hua RH Xue Ling L Zhang Wujuan W Setchell Kenneth D R KD Witte David D Grabowski Gregory A GA

Human molecular genetics 20140305 15

Gaucher disease, a prevalent lysosomal storage disease (LSD), is caused by insufficient activity of acid β-glucosidase (GCase) and the resultant glucosylceramide (GC)/glucosylsphingosine (GS) accumulation in visceral organs (Type 1) and the central nervous system (Types 2 and 3). Recent clinical and genetic studies implicate a pathogenic link between Gaucher and neurodegenerative diseases. The aggregation and inclusion bodies of α-synuclein with ubiquitin are present in the brains of Gaucher dis ...[more]

PMID: 24599400

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Project description:Background Gaucher disease (GD), a rare lysosomal storage disorder, is associated with considerable patient and caregiver burden. We examined the applicability of existing caregiver questionnaires and assessed the level of burden in caregivers of patients with GD. Methods This cross-sectional, non-interventional study was conducted in Japan. Caregivers of patients with confirmed GD (any type) were recruited (patient association group and referral) for pre-testing (May 2021) or the main survey (October–December 2021). Caregivers completed the Caregiver Impact Questionnaire (CIQ; 30 items) and Zarit Caregiver Burden Interview (ZBI; 22 items) on paper. Total CIQ and ZBI scores and subscores were determined overall and by GD type. Inter-item correlations and test-retest reliability (2 rounds, 2 weeks apart) were calculated. The relationship between caregiving duration and caregiver burden was also analyzed. Results Nine caregivers (type 2 [GD2]: n = 6; type 3 [GD3]: n = 3) and 25 caregivers (type 1 [GD1]: n = 2; GD2: n = 17; GD3: n = 6) completed the pre-test and main survey, respectively. In the main survey, mean total CIQ score, all CIQ subscores (except emotional function), and total ZBI score were highest in caregivers of patients with GD2 compared with caregivers of patients with GD1/GD3. High test-retest reliability (Kappa >0.6) was observed for 15 CIQ items and 16 ZBI items. CIQ and ZBI scores appeared to be positively correlated with each other and negatively correlated with caregiving duration. Conclusions The CIQ and ZBI are applicable, reliable measures to assess burden in caregivers of patients with GD in Japan. Caregiver burden was highest in caregivers of patients with GD2 and decreased with caregiving duration. Highlights • Gaucher disease (GD) imposes substantial burden on patients and their caregivers.• CIQ and ZBI are applicable and reliable to assess caregiver burden for GD in Japan.• Burden was highest in caregivers of patients with type 2 GD than other GD types.• Caregiver burden decreased with caregiving duration in type 2 GD.

Project description:BackgroundThe variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease.Case presentationWe report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment.ConclusionsThis case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

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Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice.

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Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice.

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