Lack of central and peripheral nervous system synuclein pathology in R1441G <i>LRRK2</i>-associated Parkinson’s disease

Vilas, Dolores; Gelpí, Ellen; Aldecoa, Ibán; Grau, Oriol; Rodriguez-Diehl, Roberta; Jaumà, Serge; Martı́, Marı́a José; Tolosa, Eduard

doi:10.1136/jnnp-2018-318473

Cited by 12 publications

(20 citation statements)

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“…14,15 Of note, there are rare cases of PD that lack LB pathology, including the R1441 and G2019S LRRK2 mutations, in which the role of synucleinopathy in disease pathogenesis is questioned. 26,27,31 There were 2 cases of G2019S LRRK2 mutation in the present BioFIND cohort: 1 PD and HC subject. Both α-synuclein SAAs showed results concordant with the clinical diagnoses.…”

Section: Discussionmentioning

confidence: 82%

“…Though the BioFIND cohort was purposely designed to reduce the chances of including genetic forms of PD, common glucocerebrosidase (GBA) and leucine repeat‐rich kinase 2 (LRRK2) variants were present in a few PD patients and HCs without PD . Based on published studies, we hypothesized that GBA mutations may increase α‐synuclein pathology whereas some LRRK2 mutations may lack α‐synuclein pathology . We had 7 PD and 2 HC subjects with pathogenic GBA variants, and 1 PD and 1 HC subject with the LRRK2 G2019S mutation.…”

Section: Resultsmentioning

confidence: 99%

“…25 Based on published studies, we hypothesized that GBA mutations may increase α-synuclein pathology whereas some LRRK2 mutations may lack α-synuclein pathology. 26,27 We had 7 PD and 2 HC subjects with pathogenic GBA variants, and 1 PD and 1 HC subject with the LRRK2 G2019S mutation. However, the assay results from these genetic variants of PD did not show any differences from subjects without established abnormal genetic variants and were concordant with their clinical diagnosis.…”

Section: Resultsmentioning

confidence: 99%

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Comparative study of cerebrospinal fluid α‐synuclein seeding aggregation assays for diagnosis of Parkinson's disease

et al. 2019

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Background PD diagnosis is based primarily on clinical criteria and can be inaccurate. Biological markers, such as α‐synuclein aggregation, that reflect ongoing pathogenic processes may increase diagnosis accuracy and allow disease progression monitoring. Though α‐synuclein aggregation assays have been published, reproducibility, standardization, and validation are key challenges for their development as clinical biomarkers. Objective To cross‐validate two α‐synuclein seeding aggregation assays developed to detect pathogenic oligomeric α‐synuclein species in CSF using samples from the same PD patients and healthy controls from the BioFIND cohort. Methods CSF samples were tested by two independent laboratories in a blinded fashion. BioFIND features standardized biospecimen collection of clinically typical moderate PD patients and nondisease controls. α‐synuclein aggregation was measured by protein misfolding cyclic amplification (Soto lab) and real‐time quaking‐induced conversion (Green lab). Results were analyzed by an independent statistician. Results Measuring 105 PD and 79 healthy control CSF samples, these assays showed 92% concordance. The areas under the curve from receiver operating characteristic curve analysis for the diagnosis of PD versus healthy controls were 0.93 for protein misfolding cyclic amplification, 0.89 for real‐time quaking‐induced conversion, and 0.95 when considering only concordant assay results. Clinical characteristics of false‐positive and ‐negative subjects were not different from true‐negative and ‐positive subjects, respectively. Conclusions These α‐synuclein seeding aggregation assays are reliable and reproducible for PD diagnosis. Assay parameters did not correlate with clinical parameters, including disease severity or duration. This assay is highly accurate for PD diagnosis and may impact clinical practice and clinical trials. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Comparative study of cerebrospinal fluid α‐synuclein seeding aggregation assays for diagnosis of Parkinson's disease

et al. 2019

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“…Neuropathological studies on PD patients harboring LRRK2 mutations have demonstrated surprisingly diverse pathology amongst patients, which has been summarized in a review by Schneider and Alcalay [136]. So far, many neuropathological studies have been conducted on autopsy samples from PD patients with LRRK2 mutations, including N1437H [18], R1441C [8,14], R1441G [16,20], Y1699C [15], G2019S [97,[137][138][139][140][141][142], and I2020T [17,19]. Although a loss of dopaminergic neurons in the substantia nigra was commonly observed amongst patients with LRRK2 mutations, the accumulation of phosphorylated α-synuclein (e.g.…”

Section: Histopathology Of Fpd Patients Harboring Lrrk2 Mutationsmentioning

confidence: 99%

“…In addition to dopaminergic neuronal loss, deposition of aggregated α-synuclein is one of the pathological hallmarks of PD brain. There have been a number of papers describing the histopathology of autopsied PD patients carrying LRRK2 mutations [14][15][16][17][18][19][20]. However, the α-synuclein pathology was surprisingly variable amongst mutation carriers, ranging from pure nigral degeneration without α-synuclein deposition, to massive deposition of α-synuclein in the cerebral cortex in addition to the midbrain.…”

Section: Introductionmentioning

confidence: 99%

Physiological and pathological functions of LRRK2: implications from substrate proteins

2018

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Leucine-rich repeat kinase 2 (LRRK2) encodes a 2527-amino acid (aa) protein composed of multiple functional domains, including a Ras of complex proteins (ROC)-type GTP-binding domain, a carboxyl terminal of ROC (COR) domain, a serine/threonine protein kinase domain, and several repeat domains. LRRK2 is genetically involved in the pathogenesis of both sporadic and familial Parkinson’s disease (FPD). Parkinson’s disease (PD) is the second most common neurodegenerative disorder, manifesting progressive motor dysfunction. PD is pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and the presence of intracellular inclusion bodies called Lewy bodies (LB) in the remaining neurons. As the most frequent PD-causing mutation in LRRK2, G2019S, increases the kinase activity of LRRK2, an abnormal increase in LRRK2 kinase activity is believed to contribute to PD pathology; however, the precise biological functions of LRRK2 involved in PD pathogenesis remain unknown. Although biochemical studies have discovered several substrate proteins of LRRK2 including Rab GTPases and tau, little is known about whether excess phosphorylation of these substrates is the cause of the neurodegeneration in PD. In this review, we summarize latest findings regarding the physiological and pathological functions of LRRK2, and discuss the possible molecular mechanisms of neurodegeneration caused by LRRK2 and its substrates.

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LRRK2 Parkinsonism: Does the Response to Gut Bacteria Mitigate the Neurological Picture?

2020

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Mutations in the leucine-rich repeat kinase 2 (LRRK2, OMIM 609007) gene were first associated with autosomal-dominant forms of Parkinson disease (PD) more than 15 years ago. Since then, at least 7 missense mutations (N1437H, R1441C/G/H, Y1699C, G2019S, I2020T) have been confirmed as pathogenic for PD, and genome-wide association studies have consistently confirmed an association between PD risk and polymorphism in LRRK2 loci. Pathogenic mutations in LRRK2 are widely regarded as the most common cause of autosomal dominantly inherited PD (PARK-LRRK2, OMIM 607060), 1 with variable age-dependent penetrance (30%-74%). 2 Here, we propose why PARK-LRRK2 should be considered a distinct, more benign form of PD. Further, we outline the crucial role of LRRK2 protein in modulating immune and infection responses, especially within the gut, and critically discuss how this might impact PARK-LRRK2 onset, progression, and pathogenesis compared with PD.

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Lack of central and peripheral nervous system synuclein pathology in R1441G LRRK2-associated Parkinson’s disease

Cited by 12 publications

References 5 publications

Comparative study of cerebrospinal fluid α‐synuclein seeding aggregation assays for diagnosis of Parkinson's disease

Comparative study of cerebrospinal fluid α‐synuclein seeding aggregation assays for diagnosis of Parkinson's disease

Physiological and pathological functions of LRRK2: implications from substrate proteins

LRRK2 Parkinsonism: Does the Response to Gut Bacteria Mitigate the Neurological Picture?

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