Probable multiple system atrophy in a German family. J Neurol Neurosurg Psychiatry 75: 924–925

Abstract: Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing. © 2006 Movement Disorder Society Key words: Parkinson's disease; genetics; LRRK2; mutation Parkinson's disease (PD) is the second most common neurodegenerative disorder. Clinical features of PD include resting tremor, rigidity, bradykinesia, and postural instability. Although quite variable, the average age of onset is 60 years. In addition, there is a slight preponderance of affected men. Pathologically, PD is characterized by the presence of Lewy bodies and progressive degeneration of neurons in the substantia nigra, pars compacta, and other brain regions. In our ongoing effort to identify additional PD susceptibility genes, we have recruited a large cohort of PD families. The control sample was collected through three sources and provided appropriate written informed consent. One sample of controls (n ϭ 52) was ascertained in Indiana, and all control subjects were examined by a single Parkinson Study Group movement disorder specialist. These control subjects completed the identical clinical evaluation as the PD sample. Individuals were considered controls if they met the following criteria: did not have a diagnosis or symptoms of PD, Alzheimer's disease (AD), stroke, or other neurological disorder; no tremor; no other first-degree family members reported to be diagnosed with PD; and no history of polio. The average age at examination of these first control subjects was 68.3 years, with a range of 55 to 82 years. All individuals were non-Hispanic Caucasians. A second control sample (n ϭ 40) was obtained from the National Cell Repository for Alzheimer's Disease. The subjects were recruited as part of an ongoing genetic initiative to make available to the research community a sample of rigorously evaluated individuals without any evidence of neurological disease. All control subjects were evaluated, and there was no evidence for either PD or dementia. The average age at examination of the second control cohort was 76.9 years, with a range of 58 to 91 years. As was the case with the first control set, all subjects from the second control set were non-Hispanic Caucasians. DNA was prepared from peripheral blood samples collected from the PD families and control subjects. The third control sample (n ϭ 276) is composed of three neurologically normal Caucasian control panels (NDPT002, NDPT006, NDPT009) obtained from the NINDS Human Genetics Resource Center at the Coriell Institute Coriell Cell Repositories (Camden, NJ). This third control sample contains 132 males and 144 females. The average age at examination of the subjects was 69.7 years, with a range of 55 to 88 years. In total, 368 neurologically normal control samples were evaluated. The guanine to adenine substitution at nucleotide 4541 of the LRRK2 cDNA that results in the R1514Q Lrrk2 (dardarin) protein variant was screened for using a newly developed TaqMan allelic-discrimination assay (Applied Biosystems). The assay was performed with 30 ng of genomic DNA from each PD subject and control individual using conditions recommended by the manufacturer and an Applied Biosystems 7300 Real Time PCR System. Of 954 affected individuals from 12 different families, 16 (1.8%) were shown to be heterozygous carriers of the R1514Q variant. In addition, 5 (1.4%) of 368 control subjects were also found to be heterozygous for the same variant similar to the frequency observed by Zimprich and associates. Discordance for the mutation among affected individuals was observed in 10 of the 13 families in which the variant was segregating. Of the 28 affected individuals in these 12 families for whom DNA was available for study, 12 of them do not carry the R1514Q variant. This finding suggests that the R1514Q variant is not segregating with PD in these families. No statistically significant difference between the R1514Q carrier group (16) and the noncarrier group (938) was detected in our analyses of numerous parameters, including age of disease onset (61.75 years in R1514Q carriers vs. 60.9 years in noncarriers), disease duration (7.18 years carriers vs. 9.53 years noncarriers), Mini-Mental State Examination score (25.62 carriers vs. 26.48 noncarriers), Blessed Functional Activity Scale (3.66 carriers vs. 4.41 noncarriers), Hoehn & Yahr (2.2 carriers vs. 2.48 noncarriers), and ethnicity. Taken together, these data suggest that the R1514Q variant is likely a nonpathogenic variant in Lrrk2 that does not contribute to the development of Parkinson disease, confirming the report of Zimprich and coworkers

Regulation of Kainate Receptor Subunit mRNA by Stress and Corticosteroids in the Rat Hippocampus

Kainate receptors are a class of ionotropic glutamate receptors that have a role in the modulation of glutamate release and synaptic plasticity in the hippocampal formation. Previous studies have implicated corticosteroids in the regulation of these receptors and recent clinical work has shown that polymorphisms in kainate receptor subunit genes are associated with susceptibility to major depression and response to anti-depressant treatment. In the present study we sought to examine the effects of chronic stress and corticosteroid treatments upon the expression of the mRNA of kainate receptor subunits GluR5-7 and KA1-2. Our results show that, after 7 days, adrenalectomy results in increased expression of hippocampal KA1, GluR6 and GluR7 mRNAs, an effect which is reversed by treatment with corticosterone in the case of KA1 and GluR7 and by aldosterone treatment in the case of GluR6. 21 days of chronic restraint stress (CRS) elevated the expression of the KA1 subunit, but had no effect on the expression of the other subunits. Similarly, 21 days of treatment with a moderate dose of corticosterone also increased KA1 mRNA in the dentate gyrus, whereas a high corticosterone dose has no effect. Our results suggest an interaction between hippocampal kainate receptor composition and the hypothalamic-pituitary-adrenal (HPA) axis and show a selective chronic stress induced modulation of the KA1 subunit in the dentate gyrus and CA3 that has implications for stress-induced adaptive structural plasticity

Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics

Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies

Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA