Mathias Toft

Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.

Lrrk2 and lewy body disease

The Lrrk2 kinase domain G2019S substitution is the most common genetic basis of familial and sporadic parkinsonism. Patients harboring the G2019S substitution usually present with clinical Parkinsons disease.

Clinical features of LRRK2-associated Parkinson's disease in central Norway.

Several pathogenic mutations in the leucine‐rich repeat kinase 2 (LRRK2; PARK8) gene recently have been identified in familial and sporadic parkinsonism. We screened 435 Norwegian patients diagnosed with Parkinsons disease and 519 control subjects for the presence of 7 LRRK2 mutations. Nine patients from seven families were found to be heterozygote carriers of the LRRK2 6055G>A (G2019S) mutation. Twelve of 28 first‐degree relatives also carried the mutation, but only 1 had Parkinsons disease. The clinical features included asymmetric resting tremor, bradykinesia, and rigidity with a good response to levodopa and could not be distinguished from idiopathic Parkinsons disease. Ann Neurol 2005;57:762–765

Glucocerebrosidase gene mutations and Parkinson disease in the Norwegian population

An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson disease (PD) was recently reported in Ashkenazi Jews. The authors screened a series of 311 Norwegian patients with PD and 474 controls for 2 common functional mutations of the GBA protein, N370S and L444P. Seven patients (2.3%) and 8 controls (1.7%) carried a mutant GBA allele (p = 0.58). This study does not indicate increased susceptibility to PD in GBA mutations carriers in Norway.

Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinsons disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimers disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinsons disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta‐analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total‐tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10−25). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF‐total‐tau (P = .0110) but not Aβ42 suggesting that TREM2s role in AD may involve tau dysfunction.

Novel Pathogenic LRRK2 p.Asn1437His Substitution in Familial Parkinson's Disease

Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism.

Multiple alpha-synuclein gene polymorphisms are associated with Parkinson's disease in a Norwegian population

Objectives –  Previous studies have found associations between Parkinson’s disease (PD) and polymorphisms located within both the alpha‐synuclein gene (SNCA) promoter and other gene regions. Our aim was to study SNCA gene markers in a closely matched Norwegian PD population to examine the genetic relationship between different polymorphisms associated with the disease.

MAPK-pathway activity, Lrrk2 G2019S, and Parkinson's disease

The 6055G>A mutation in the leucine‐rich repeat kinase 2 (LRRK2) gene results in a G2019S substitution in the mixed‐lineage kinase domain of Lrrk2, causing autosomal dominant Parkinsons disease (PD). We hypothesized the mutation alters cellular mitogen‐activated protein kinase (MAPK) signalling cascades, and might be detectable in tissues other than in the brain. We therefore compared total levels and activation of the signalling proteins Src, HSP27, p38 MAPK, JNK, and ERK, in extracts of leukocytes isolated from patients with PD carrying the G2019S mutation, healthy mutation carriers, patients with idiopathic PD, and healthy controls. Phosphorylation of Src, HSP27, and JNK was reduced significantly in cell extracts from patients with G2019S‐associated PD compared to healthy controls. Similarly, phosphorylation was reduced significantly in Src and HSP27 in the group of healthy carriers of the mutation, as well as in patients with idiopathic PD. Significant reductions in total Src were also observed in these three groups compared to the controls. The results of this pilot project therefore indicate significant alterations in key signalling proteins in leukocytes from patients with PD, and were most pronounced in G2019S‐associated PD. Changes in MAPK‐signalling may thus be common to PD pathophysiology, regardless of aetiology. Such changes may also be shown in blood samples during the preclinical stage of LRRK2‐associated PD, which could be particularly important for the development of neuroprotective strategies to delay onset, or slow progression of PD.

Genomewide Association, Parkinson Disease, and PARK10

The authors thank the patients and families for their participation in this study. Mayo Clinic Jacksonville is an M. K. Udall Parkinson’s Disease Research Center of Excellence (National Institute of Neurological Disorders and Stroke grant P01 NS40256), and the authors thank all collaborators at the Udall Center. This study was also supported by the National Institutes of Health grant R01 NS36960, the Research Council of Norway grant 153487/V50, and Reberg’s Legacy. The Ireland research consortium was supported by a Programme for Research in Third-Level Institutions neurosciences award and by the Research and Development Office of the Health and Personal Social Services. O.A.R. and M.T. are partly funded by National Parkinson Foundation and Parkinson’s Disease Foundation fellowships, respectively. We thank Minnie Schreiber for technical assistance.