Association of Dual <i>LRRK2 </i>G2019S and <i>GBA</i> Variations With Parkinson Disease Progression

Ortega, Roberto A.; Wang, Cuiling; Raymond, Deborah; Bryant, Nicole; Scherzer, Clemens R.; Thaler, Avner; Alcalay, Roy N.; West, Andrew B.; Mirelman, Anat; Kuras, Yuliya I.; Marder, Karen; Giladi, Nir; Ozelius, Laurie J.; Bressman, Susan; Saunders‐Pullman, Rachel

doi:10.1001/jamanetworkopen.2021.5845

Cited by 56 publications

(38 citation statements)

References 47 publications

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“…A study with a cohort of 236 participants showed that the LRRK2 mutation together with GBA rescued from further mental degeneration [150]. Meanwhile, a recent study with a cohort of 1193 Ashkenazi Jewish population showed no differences between genotypes [151].…”

Section: Lrrk2mentioning

confidence: 99%

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

et al. 2021

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Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson’s disease.

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Section: Lrrk2mentioning

confidence: 99%

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

et al. 2021

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“…It would be anticipated that having a mutation in both LRRK2 and GBA would have an added deleterious effect, as suggested by laboratory studies [ 146 , 147 ]. However, a recent longitudinal study of a large PD sample measuring progression using the Montreal Cognitive Assessment and Movement Disorders Society—Unified Parkinson Disease Rating Scale–Part III, showed that patients with both the p.G2019S mutation and GBA -PD had a slower rate of decline than those with GBA -PD alone, which was no different from LRRK2 -G2019S alone [ 148 ]. Similarly, a retrospective observational study of Ashkenazi Jewish patients revealed that patients with mutations in LRRK2 and GBA (described by the authors as “ GBA - LRRK2 -PD”) were less frequently affected by dementia, probable REM-behavior sleep disorder, and psychosis, compared to other groups ( GBA -PD, LRRK2 -PD, mutation-negative PD) [ 149 ].…”

Section: Dual Lrrk2 and Gba Mutation Carriersmentioning

confidence: 99%

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

Jia

Fellner

Kumar

2022

Genes

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Parkinson’s disease may be caused by a single pathogenic variant (monogenic) in 5–10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and ethnic distribution. Well-established Parkinson’s disease genes include autosomal dominant forms (SNCA, LRRK2, and VPS35) and autosomal recessive forms (PRKN, PINK1 and DJ1). Furthermore, mutations in the GBA gene are a key risk factor for Parkinson’s disease, and there have been major developments for X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism may be due to mutations in genes such as ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, and SYNJ1. Furthermore, numerous genes have recently been implicated in Parkinson’s disease, such as CHCHD2, LRP10, TMEM230, UQCRC1, and VPS13C. Additionally, we discuss the role of heterozygous mutations in autosomal recessive genes, the effect of having mutations in two Parkinson’s disease genes, the outcome of deep brain stimulation, and the role of genetic testing. We highlight that monogenic Parkinson’s disease is influenced by ethnicity and geographical differences, reinforcing the need for global efforts to pool large numbers of patients and identify novel candidate genes.

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“…In a larger study, 27 dual mutation patients (all with LRRK2 G2019S and a majority with mild GBA mutations) have significantly better motor function, lower rates of dementia and slower cognitive decline than both mild and severe GBA mutation carriers, again implying a modifying role of LRRK2 on motor and nonmotor phenotypes of patients with GBA mutations [ 94 ]. Combining data from multiple studies, Ortega and colleagues showed that GBA- PD (containing similar proportions of patients with mild and severe GBA mutation to the dual mutation group) have the fastest motor and cognitive decline compared with LRRK2 -PD, PD with dual mutations and iPD, while the latter three groups are similar on this aspect [ 95 ]. Data concerning the age of onset of LRRK2-GBA dual mutation carriers are conflicting.…”

Section: Dual Lrrk2-gba Mutations In Pd Patientsmentioning

confidence: 99%

“…Data concerning the age of onset of LRRK2-GBA dual mutation carriers are conflicting. Two studies reported that PD patients with LRRK2-GBA dual mutations were younger at first motor symptom onset than single mutation carriers [ 93 , 96 ], while no such differences were found in two other studies [ 94 , 95 ].…”

Section: Dual Lrrk2-gba Mutations In Pd Patientsmentioning

confidence: 99%

LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson's disease

Pang

et al. 2022

Transl Neurodegener

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Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

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Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression

Cited by 56 publications

References 47 publications

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson's disease

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