The role of glucocerebrosidase in Parkinson disease pathogenesis

Gegg, Matthew E.; Schapira, Anthony H.V.

doi:10.1111/febs.14393

Cited by 107 publications

(85 citation statements)

References 135 publications

(238 reference statements)

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“…Multiple studies have established a link between mutations in GBA1 and PD (Gegg & Schapira, 2018;Lesage et al, 2011;Sidransky et al, 2009;Winder-Rhodes et al, 2013). Although underlying mechanisms and pathways have been pursued, the basis for this association is not fully understood.…”

Section: Parkinson Diseasementioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common diseases like Parkinson disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments.

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Section: Parkinson Diseasementioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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“…Whereas homozygous GBA mutation cause Gaucher disease (GD), GBA heterozygosity is a potential risk factor for developing PD with an earlier age of onset and a major risk to develop dementia compared to idiopathic PD [17]. Moreover, recent studies showed that GBA heterozygous mutation is linked with dysfunction in mitophagy [18,19].…”

Section: Introductionmentioning

confidence: 99%

In Vivo Mitochondrial Function in Idiopathic and Genetic Parkinson’s Disease

2019

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Parkinson's disease (PD) is associated with brain mitochondrial dysfunction. High-energy phosphates (HEPs), which rely on mitochondrial functioning, may be considered potential biomarkers for PD. Phosphorus magnetic resonance spectroscopy ( 31 P-MRS) is a suitable tool to explore in vivo cerebral energetics. We considered 10 31 P-MRS studies in order to highlight the main findings about brain energetic compounds in patients affected by idiopathic PD and genetic PD. The studies investigated several brain areas such as frontal lobes, occipital lobes, temporoparietal cortex, visual cortex, midbrain, and basal ganglia. Resting-state studies reported contrasting results showing decreased as well as normal or increased HEPs levels in PD patients. Functional studies revealed abnormal PCr + βATP levels in PD subjects during the recovery phase and abnormal values at rest, during activation and recovery in one PD subject with PINK1 gene mutation suggesting that mitochondrial machinery is more impaired in PD patients with PINK1 gene mutation. PD is characterized by energetics impairment both in idiopathic PD as well as in genetic PD, suggesting that mitochondrial dysfunction underlies the disease. Studies are still sparse and sometimes contrasting, maybe due to different methodological approaches. Further studies are needed to better assess the role of mitochondria in the PD development.

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“…Heterozygous mutations in progranulin cause NCL (Smith, Damiano, et al, 2012) Null mutation in GRN gene decreases the release of exosomes (Benussi et al, 2016) Gaucher disease GBA GBA encodes beta-glucosidase, a lysosomal enzyme. GBA mutations also increase the risk to PD (Gegg & Schapira, 2018) Undetermined TA B L E 1 (Continued) of CAG nucleotide repeats in the gene huntingtin. The number of CAG repeats determines the median age of onset, ranging from 27 to 66 years (Brinkman, Mezei, Theilmann, Almqvist, & Hayden, 1997).…”

Section: )mentioning

confidence: 99%

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

Guix

2019

J of Neuroscience Research

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The finding of an effective cure or treatment for neurodegenerative diseases is one of the biggest challenges for this century. Although these diseases show different clinical manifestations, the presence of toxic protein aggregates in the brain of patients is a common feature to all of them, suggesting a loss of protein homeostasis.Aging, the primary risk factor for the majority of neurodegenerative disorders, is linked to the impairment of degradative compartments such as lysosomes and autophagosomes. Besides, many genetic factors for Alzheimer's disease, Parkinson's disease, or frontotemporal dementia, as examples of frequent neurodegenerative diseases, are causative of endo-lysosomal and autophagosomal dysfunctions. There is scientific evidence suggesting that neurons can counteract the accumulation of undegraded cellular material by the secretion of extracellular vesicles (EVs), which are vesicles with a size ranging from 50 to 100 nm generated in a type of endosomal compartment named multivesicular body. EVs play a crucial role in removing cellular waste, promoting protein aggregation, and spreading toxic protein aggregates in the brain of patients. In this review, the interplay between the impairment of degradative compartments, the secretion of EVs, and their pathological/beneficial role in neurodegeneration is described.

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The role of glucocerebrosidase in Parkinson disease pathogenesis

Cited by 107 publications

References 135 publications

Exploring genetic modifiers of Gaucher disease: The next horizon

Exploring genetic modifiers of Gaucher disease: The next horizon

In Vivo Mitochondrial Function in Idiopathic and Genetic Parkinson’s Disease

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

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