Glucocerebrosidase mutations: A paradigm for neurodegeneration pathways

Vieira, Sophia R.L.; Schapira, Anthony H.V.

doi:10.1016/j.freeradbiomed.2021.08.230

Cited by 17 publications

(9 citation statements)

References 217 publications

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“…Some of the experimentally validated and putative CaMBP risk proteins analyzed here for PD, HD, LBD, and ALS/FTD also are interlinked ( Figure 1 ). For example, the LBD risk factors GBA and TMEM175 have also been linked to ALS/FTD and PD [ 56 ]. SQUSTM1, an ALS/FTD risk factor, has been shown to be involved in both HD and PD [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Calmodulin Binding Domains in Critical Risk Proteins Involved in Neurodegeneration

O’Day

2022

CIMB

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Neurodegeneration leads to multiple early changes in cognitive, emotional, and social behaviours and ultimately progresses to dementia. The dysregulation of calcium is one of the earliest potentially initiating events in the development of neurodegenerative diseases. A primary neuronal target of calcium is the small sensor and effector protein calmodulin that, in response to calcium levels, binds to and regulates hundreds of calmodulin binding proteins. The intimate and entangled relationship between calmodulin binding proteins and all phases of Alzheimer’s disease has been established, but the relationship to other neurodegenerative diseases is just beginning to be evaluated. Risk factors and hallmark proteins from Parkinson’s disease (PD; SNCA, Parkin, PINK1, LRRK2, PARK7), Huntington’s disease (HD; Htt, TGM1, TGM2), Lewy Body disease (LBD; TMEM175, GBA), and amyotrophic lateral sclerosis/frontotemporal disease (ALS/FTD; VCP, FUS, TDP-43, TBK1, C90rf72, SQSTM1, CHCHD10, SOD1) were scanned for the presence of calmodulin binding domains and, within them, appropriate binding motifs. Binding domains and motifs were identified in multiple risk proteins, some of which are involved in multiple neurodegenerative diseases. The potential calmodulin binding profiles for risk proteins involved in HD, PD, LBD, and ALS/FTD coupled with other studies on proven binding proteins supports the central and potentially critical role for calmodulin in neurodegenerative events.

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Section: Discussionmentioning

confidence: 99%

Calmodulin Binding Domains in Critical Risk Proteins Involved in Neurodegeneration

O’Day

2022

CIMB

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“…F213I mutation, the A-to-T transversion at nt 754 in exon 6 (NM_000157.4: c.754T > A), is also named F252I (p.Phe252Ile) according to the new nomenclature and is the second common point mutant GBA1 allele in Chinese GD patients ( He et al, 1992 ; Zhang et al, 2009 ; Oto et al, 2021 ). The F213I mutation was found in all three types of GD, and F213I-associated types 2 GD and type 3 GD were more prevalent in Asian populations ( Koprivica et al, 2000 ; Tajima et al, 2009 ; Zhang et al, 2009 ; Vieira and Schapira, 2021 ).…”

Section: Introductionmentioning

confidence: 94%

Establishment and Phenotypic Analysis of the Novel Gaucher Disease Mouse Model With the Partially Humanized Gba1 Gene and F213I Mutation

et al. 2022

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Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA1 gene, which produces the glucocerebrosidase (GCase) protein. There are more than 500 mutations reported in GBA1, among which L444P (p.Leu444Pro) and F213I (p.Phe213Ile) are the most common in the Chinese population, while the function of F213I mutation remains elusive. This study aims to establish the GD mouse model of partially humanized Gba1 gene with F213I mutation. In vitro GCase activity assays showed that the product of partially humanized Gba1 gene, in which the mouse exons 5-7 were replace by the corresponding human exons, displayed similar activity with the wild-type mouse Gba1, while the F213I mutation in the humanized Gba1 led to significant decrease in enzyme activity. ES cell targeting was used to establish the mice expressing the partially humanized Gba1-F213I. Gba1F213I/+ mice did not show obviously abnormal phenotypes, but homozygous Gba1F213I/F213I mice died within 24 h after birth, whose epidermal stratum corneum were abnormal from the wild-type. The GCase activity in Gba1F213I/F213I mice greatly decreased. In conclusion, our results showed that the partially humanized GD mouse model with the F213I mutation was developed and homozygous F213I mutation is lethal for newborn mice.

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“…Additionally, carriers of GBA variants also display an earlier disease onset (<50 years), a three-fold increased risk to develop dementia and a more rapid disease course compared to non-carriers [ 67 , 68 ]. Despite extensive research, the molecular and cellular mechanisms underlying the high PD risk observed in carriers of GBA mutations remain to be elucidated [ 69 ].…”

Section: The Genetic Landscape Of Parkinson’s Disease: a Brief Overviewmentioning

confidence: 99%

Psychosis in Parkinson’s Disease: A Lesson from Genetics

Angelopoulou

Bougea

Papageorgiou

et al. 2022

Genes

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Psychosis in Parkinson’s disease (PDP) represents a common and debilitating condition that complicates Parkinson’s disease (PD), mainly in the later stages. The spectrum of psychotic symptoms are heterogeneous, ranging from minor phenomena of mild illusions, passage hallucinations and sense of presence to severe psychosis consisting of visual hallucinations (and rarely, auditory and tactile or gustatory) and paranoid delusions. PDP is associated with increased caregiver stress, poorer quality of life for patients and carers, reduced survival and risk of institutionalization with a significant burden on the healthcare system. Although several risk factors for PDP development have been identified, such as aging, sleep disturbances, long history of PD, cognitive impairment, depression and visual disorders, the pathophysiology of psychosis in PD is complex and still insufficiently clarified. Additionally, several drugs used to treat PD can aggravate or even precipitate PDP. Herein, we reviewed and critically analyzed recent studies exploring the genetic architecture of psychosis in PD in order to further understand the pathophysiology of PDP, the risk factors as well as the most suitable therapeutic strategies.

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Glucocerebrosidase mutations: A paradigm for neurodegeneration pathways

Cited by 17 publications

References 217 publications

Calmodulin Binding Domains in Critical Risk Proteins Involved in Neurodegeneration

Calmodulin Binding Domains in Critical Risk Proteins Involved in Neurodegeneration

Establishment and Phenotypic Analysis of the Novel Gaucher Disease Mouse Model With the Partially Humanized Gba1 Gene and F213I Mutation

Psychosis in Parkinson’s Disease: A Lesson from Genetics

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