The emerging role of LRRK2 in tauopathies

Herbst, Susanne; Lewis, Patrick A.; Morris, Huw R.

doi:10.1042/cs20220067

Cited by 15 publications

(16 citation statements)

References 64 publications

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“…The third genome-wide significant SNP was rs17442721 in the noncoding RNA LINC02555 , which was protective against developing dementia (OR = 0.43, 95% CI = 0.32 - 0.57, P = 1.44e 08). LINC02555 is potentially a regulatory locus for LRRK2 expression in specific cell types [41] and may mediate PSP survival [42]. However, this SNP is in LD with LRRK2 G2019S (rs34637584, r2 = 0.54, D’ = 0.97).…”

Section: Resultsmentioning

confidence: 99%

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Wu,

Real,

Martinez

et al. 2023

Preprint

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Up to 80% of Parkinsons disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinsons disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinsons disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinsons disease and dementia with Lewy bodies/Parkinsons disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinsons (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.

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Section: Resultsmentioning

confidence: 99%

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Wu,

Real,

Martinez

et al. 2023

Preprint

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“…Moreover, the pathological pathway from the PSP evolution variant to LRRK2 could be explained by the effect of LINC02555 on the expression or translation of LRRK2 mRNA in specific cells, thus increasing LRRK2 protein titles [ 105 ]. However, it remains to be confirmed whether the PSP-linked variant provokes hyperactive LRRK2 kinase and Rab phosphorylation [ 108 ]. The identification of diverse patterns of Rab phosphorylation in future research may result in new therapeutic options for PSP.…”

Section: Discussionmentioning

confidence: 99%

Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

Bougea

2023

IJMS

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Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are uncommon multifactorial atypical Parkinsonian syndromes, expressed by various clinical features. MSA and PSP are commonly considered sporadic neurodegenerative disorders; however, our understanding is improving of their genetic framework. The purpose of this study was to critically review the genetics of MSA and PSP and their involvement in the pathogenesis. A systemized literature search of PubMed and MEDLINE was performed up to 1 January 2023. Narrative synthesis of the results was undertaken. In total, 43 studies were analyzed. Although familial MSA cases have been reported, the hereditary nature could not be demonstrated. COQ2 mutations were involved in familial and sporadic MSA, without being reproduced in various clinical populations. In terms of the genetics of the cohort, synuclein alpha (SNCA) polymorphisms were correlated with an elevated likelihood of manifesting MSA in Caucasians, but a causal effect relationship could not be demonstrated. Fifteen MAPT mutations were linked with PSP. Leucine-rich repeat kinase 2 (LRRK2) is an infrequent monogenic mutation of PSP. Dynactin subunit 1 (DCTN1) mutations may imitate the PSP phenotype. GWAS have noted many risk loci of PSP (STX6 and EIF2AK3), suggesting pathogenetic mechanisms related to PSP. Despite the limited evidence, it seems that genetics influence the susceptibility to MSA and PSP. MAPT mutations result in the MSA and PSP pathologies. Further studies are crucial to elucidate the pathogeneses of MSA and PSP, which will support efforts to develop novel drug options.

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“…While Lewy bodies and loss of SNc neurons are the main pathological hallmarks across PD, an overrepresentation of tau pathology has been reported in LRRK2 PD cases (Henderson et al, 2019;Herbst et al, 2022;Ujiie et al, 2012;Zimprich et al, 2004). A recent GWAS linked genetic variation in the LRRK2 locus to survival in progressive supranuclear palsy (PSP) (Jabbari et al, 2021), further highlighting a role for LRRK2 in tau pathology.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with other opposing phenotypes linked to these two LRRK2 substrates, we found features of α-synuclein homeostasis altered in Rab8a but not Rab10 KO neurons, with selective effects on Tau in Rab10 but not Rab8a KO neurons. These data not only identify distinct cellular pathways that likely contribute to the unique pleiomorphic pathology associated with LRRK2-PD, but may also address why co-morbid α-synuclein and tau pathology is not reported (Henderson et al, 2019;Herbst et al, 2022;Ujiie et al, 2012;Zimprich et al, 2004).…”

Section: Introductionmentioning

confidence: 93%

“…LRRK2 is a large, 2,527 amino acid protein with functional GTPase and kinase domains where the PD-linked mutations largely cluster (Kluss et al, 2019). Upon neuropathologic examination, LRRK2-PD can manifest with pure nigral degeneration (rare) or classic Lewy body pathology typical of idiopathic PD, but surprisingly a majority of cases show deposition of tau into neurofibrillary tangles (Henderson et al, 2019;Herbst et al, 2022;Ujiie et al, 2012;Zimprich et al, 2004). How LRRK2 pathobiology might provoke distinct and independent neuropathological features is one of the greatest unanswered questions in the field.…”

Section: Introductionmentioning

confidence: 99%

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The LRRK2 kinase substrates Rab8a and Rab10 contribute complementary but distinct disease-relevant phenotypes in human neurons

Mamais

Sanyal

Fajfer

et al. 2023

Preprint

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Mutations in the LRRK2 gene cause familial Parkinson's disease presenting with pleomorphic neuropathology that can involve α-synuclein or tau accumulation. LRRK2 mutations are thought to converge toward a pathogenic increase in LRRK2 kinase activity. A subset of small Rab GTPases have been identified as LRRK2 substrates, with LRRK2-dependent phosphorylation resulting in Rab inactivation. We used CRISPR/Cas9 genome editing to generate a novel series of isogenic iPSC lines deficient in the two most well validated LRRK2 substrates, Rab8a and Rab10, from two independent, deeply phenotyped healthy control lines. Thorough characterization of NGN2-induced neurons revealed divergent effects of Rab8a and Rab10 deficiency on lysosomal pH, LAMP1 association with Golgi, α-synuclein insolubility and tau phosphorylation, while parallel effects on lysosomal numbers and Golgi clustering were observed. Our data demonstrate largely antagonistic effects of genetic Rab8a or Rab10 inactivation which provide discrete insight into the pathologic features of their biochemical inactivation by pathogenic LRRK2 mutation.

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The emerging role of LRRK2 in tauopathies

Cited by 15 publications

References 64 publications

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

The LRRK2 kinase substrates Rab8a and Rab10 contribute complementary but distinct disease-relevant phenotypes in human neurons

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