Mutations in glucocerebrosidase are a major genetic risk factor for Parkinson’s disease and increase susceptibility to dementia in a Flanders-Belgian cohort

Crosiers, David; Verstraeten, Aline; Wauters, Eline; Engelborghs, Sebastiaan; Peeters, Karin; Mattheijssens, Maria; Deyn, Peter Paul De; Theuns, Jessie; Broeckhoven, Christine Van; Cras, Patrick

doi:10.1016/j.neulet.2016.07.008

Cited by 25 publications

(24 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GBA1 mutations greatly increase the risk of incident dementia. 10,47,49,60,64,66,69,74,[77][78][79][80][81][82] The risk of cognitive impairment in GBA1 mutation carriers is 2.4to 3-fold higher than in noncarriers. 49,83 In turn, the risk for dementia in PD carriers of severe mutations is 2-to 3-fold higher than that in carriers of mild mutations.…”

Section: Nonmotor Symptomsmentioning

confidence: 99%

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

View full text Add to dashboard Cite

Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α‐synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α‐synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α‐synuclein, the GBA1 mutation‐associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society

show abstract

Section: Nonmotor Symptomsmentioning

confidence: 99%

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

View full text Add to dashboard Cite

show abstract

“…GCase is involved in sphingolipid metabolism by catalyzing the breakdown of glucosylceramide (GluCer) and glucosylsphingosine (GluSph) to ceramide and sphingosine respectively in the lysosome [15,30]. Up to 7-12% of PD patients carry mutations in GBA1, and hence GBA1 is the most common genetic risk factor [23,30,100].…”

Section: Introductionmentioning

confidence: 99%

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

et al. 2020

Self Cite

View full text Add to dashboard Cite

Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synucleinpositive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.Keywords Parkinson's disease · Massive parallel sequencing · ATP10B P-type ATPase · Endo-lysosomal lipid flippase · Loss-of-function · Glucosylceramide Shaun Martin and Stefanie Smolders shared first authors and have contributed equally. Peter Vangheluwe and Christine Van Broeckhoven shared last and corresponding authors and have contributed equally.

show abstract

“…The risk of PD for heterozygous mutation carriers ranges from 2.2% to 5% by age 65 to 10.9%–15% by the age of 85 (McNeill et al, 2012a; Rana et al, 2013). GBA -related PD ( GBA -PD) is overall associated with more prominent cognitive decline than idiopathic PD (Alcalay et al, 2012; Brockmann et al, 2011; Saunders-Pullman et al, 2010; Schapira, 2015; Sidransky et al, 2009; Winder-Rhodes et al, 2013), including an increased risk for both mild cognitive impairment (Alcalay et al, 2012) and dementia (Brockmann et al, 2011; Crosiers et al, 2016; Mata et al, 2016; Seto-Salvia et al, 2012). This includes worse performance on broad screening measures of cognitive functioning (e.g., the Montreal Cognitive Assessment; Brockmann et al, 2011), and more specifically, deficits in visual short-term memory (Zokaei et al, 2014), memory and visuospatial functioning (Alcalay et al, 2012; Mata et al, 2016), and executive functioning and working memory (Mata et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Cognitive and motor functioning in elderly glucocerebrosidase mutation carriers

Moran

Wang

Katz

et al. 2017

Neurobiology of Aging

View full text Add to dashboard Cite

Mutations in the glucocerebrosidase (GBA) gene are a strong genetic risk factor for the development of Parkinson’s disease and dementia with Lewy Bodies. However the penetrance of GBA mutations is low for these diseases in heterozygous carriers. The aim of this study was to examine the relationship between mutation status and cognitive and motor functioning in a sample of community-dwelling older adults. Using linear mixed effects models, we examined the effect of heterozygous mutation status on 736 community-dwelling older adults (≥70 years) without dementia or Parkinson’s disease assessed over an average of 6 years, 28 of whom had a single GBA mutation (primarily N370S). Verbal memory was measured using the picture version of the Free and Cued Selective Reminding Test, and carriers showed significantly (p < 0.05) greater decline in verbal memory over time. There was no difference in motor function or any other cognitive domain. Taken together, these results suggest an effect, but an overall limited burden, of harboring a single GBA mutation in aging mutation carriers.

show abstract

Mutations in glucocerebrosidase are a major genetic risk factor for Parkinson’s disease and increase susceptibility to dementia in a Flanders-Belgian cohort

Cited by 25 publications

References 35 publications

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

Cognitive and motor functioning in elderly glucocerebrosidase mutation carriers

Contact Info

Product

Resources

About