Lack of Familial Aggregation of the "Essential Tremor-Plus" Phenotype in Familial Essential Tremor.

BACKGROUND: Essential tremor (ET) is a highly prevalent neurological disease that frequently runs in families. A recent and controversial proposal is to separate ET patients into two distinct groups - ET versus ET-plus. If this were a valid construct, one would expect in familial aggregation studies to observe that ET-plus would cluster in some families yet be absent in others, rather than being randomly distributed across families. We examined whether there is evidence of familial aggregation of ET-plus. METHODS: Probands (n = 84 [56 ET-plus and 28 ET]) and their first- and second-degree relatives (n = 182 and 48) enrolled in a genetics study. χ2 and generalized estimating equations (GEE) tested associations between probands' ET-plus status and the ET-plus status of their relatives. RESULTS: χ2 analyses revealed that ET-plus was no more prevalent in relatives of probands diagnosed with ET-plus than in relatives of probands diagnosed with ET, p > 0.05. Restricting relatives to first-degree relatives similarly did not detect a significant association (p = 0.88). GEE yielded similar results (respective p's = 0.39 and 0.81). CONCLUSION: The data demonstrate that ET-plus does not seem to aggregate in families. As such, they do not lend support to the notion that ET-plus is a valid biological construct.

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.

BACKGROUND: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. METHODS: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed. RESULTS: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome. CONCLUSIONS: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Current Opinions and Consensus for Studying Tremor in Animal Models.

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.

High-depth whole genome sequencing of an Ashkenazi Jewish reference panel: enhancing sensitivity, accuracy, and imputation.

While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (≥ 30×), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population. We developed a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population. Quality control (QC) thresholds for the Illumina X Ten platform were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. QC procedures also identified numerous regions that are poorly mapped using current reference or alternate assemblies. After stringent QC, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels, especially in the range of rare variants that may be most critical to further progress in mapping of complex phenotypes. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.

A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder.

In 1994 in the Journal of Cell Science, Hennekes and Nigg reported that changing valine to arginine at the endoproteolytic cleavage site in chicken prelamin A abolishes its conversion to lamin A. The consequences of this mutation in an organism have remained unknown. We now report that the corresponding mutation in a human subject leads to accumulation of prelamin A and causes a progeroid disorder. Next generation sequencing of the subject and her parents' exomes identified a de novo mutation in the lamin A/C gene (LMNA) that resulted in a leucine to arginine amino acid substitution at residue 647 in prelamin A. The subject's fibroblasts accumulated prelamin A, a farnesylated protein, which led to an increased percentage of cultured cells with morphologically abnormal nuclei. Treatment with a protein farnesyltransferase inhibitor improved abnormal nuclear morphology. This case demonstrates that accumulation of prelamin A, independent of the loss of function of ZMPSTE24 metallopeptidase that catalyzes processing of prelamin A, can cause a progeroid disorder and that a cell biology assay could be used in precision medicine to identify a potential therapy.

Genome-wide association study in essential tremor identifies three new loci.

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

The effect of MAPT haplotype on neocortical Lewy body pathology in Parkinson disease.

The H1 haplotype of the microtubule-associated protein tau gene (MAPT) is associated with an increased risk of Parkinson disease (PD) compared with the H2 haplotype, but its effect on Lewy body (LB) formation is unclear. In this study, we compared the MAPT haplotype frequency between pathologically confirmed PD patients (n = 71) and controls (n = 52). We analyzed Braak LB stage, Braak neurofibrillary tangle (NFT) stage, and CERAD amyloid score by haplotype. We further tested the association between MAPT haplotype and semi-quantitative counts of LBs, NFTs, and neuritic plaques (NPs) in multiple neocortical regions. Consistent with previous reports, PD cases had an increased likelihood of carrying an H1/H1 genotype compared to controls (OR = 5.72, 95 % CI 1.80-18.21, p = 0.003). Braak LB, Braak NFT and CERAD scores did not differ by haplotype. However, H1/H1 carriers had higher LB counts in parietal cortex (p = 0.02) and in overall neocortical LBs (p = 0.03) compared to non-H1/H1 cases. Our analyses suggest that PD patients homozygous for the H1 haplotype have a higher burden of neocortical LB pathology.

Copy-number disorders are a common cause of congenital kidney malformations.

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

The relationship between obsessive-compulsive symptoms and PARKIN genotype: The CORE-PD study.

BACKGROUND: Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS). METHODS: The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers. RESULTS: Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13). CONCLUSIONS: First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.

Familial versus Sporadic Essential Tremor: What Patterns Can One Decipher in Age of Onset?

BACKGROUND: Essential tremor (ET) is a very prevalent neurological disease. Although familial and sporadic ET cases are assumed to have different age at onset distributions, no detailed study of this question has been carried out. METHODS: Using a carefully characterized sample of 376 ET cases (232 (61.7%) familial) enrolled in a clinical-epidemiological study, we contrasted the age of onset distributions in familial versus sporadic ET. RESULTS: Familial ET had a lower age at onset distribution, regardless of the current age. The majority (71 (86.6%) of 82) of ET cases that appeared during childhood were familial rather than sporadic. Additionally, the onset of ET occurred after age 40 in a majority of cases (125 (53.9%) of 232 with familial ET and 118 (81.9%) of 144 with sporadic ET), and in approximately one-quarter to one-half of cases, after age 60. CONCLUSIONS: The age of onset of ET differs between familial and sporadic ET and furthermore, is variable within each of these groups. The onset of ET during childhood is usually familial, and the small number of identified exceptions could be due to de novo mutations. Understanding the heterogeneity in onset age will provide insights into the nature of underlying etiological and patho-biological processes about which little is presently known.

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci.

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

Parkinson's disease with Lewy bodies associated with a heterozygous PARKIN dosage mutation.

BACKGROUND: PARKIN-related disease remains incompletely understood. First, the pathogenicity of heterozygous PARKIN mutations is unclear, although some evidence supports causality. Second, unlike sporadic Parkinson's disease (PD), Lewy bodies are present only in a minority of cases. Only one other heterozygote PARKIN carrier with autopsy findings has been described. Our case adds to the broadening pathological and clinical phenotype of PARKIN-related disease. METHODS: Clinical chart, genetic analysis, and pathological findings of a patient with familial PD are reviewed. RESULTS: A 44-year-old man developed slowly progressive tremor-predominant PD with excellent response to levodopa. Genetic analysis revealed a heterozygous PARKIN exon 3-4 deletion, also present in 2 family members with early-onset PD. Postmortem examination showed severe neuronal loss in the substantia nigra and nucleus coeruleus with the presence of diffuse Lewy bodies. CONCLUSIONS: The deletion is unlikely an incidental finding considering family history, age at onset, and the presence of clinical and pathological features not typical of sporadic PD.

Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2.

OBJECTIVE: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility. METHODS: A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls). RESULTS: Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes. INTERPRETATION: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.

Familial aggregation of cranial tremor in familial essential tremor.

BACKGROUND: Essential tremor (ET) is often familial and phenotypic features may be shared within families. Cranial (neck, voice, and jaw) tremor is an important feature of ET. We examined whether cranial tremor aggregates in ET families, after controlling for other factors (age, tremor severity, and duration). METHODS: Among ET probands and relatives enrolled in a genetic study at Columbia University (95 subjects in 28 families), we assessed the degree to which occurrence of cranial tremor in the proband predicted occurrence of cranial tremor in affected relatives. RESULTS: Forty-five (47.4%) subjects had cranial tremor on neurological examination (probands 66.7%, relatives 39.7%). Among 28 families, 23 (82.1%) contained individuals with and individuals without cranial tremor, indicating a high degree of within-family heterogeneity. In comparison to subjects without cranial tremor, those with cranial tremor had higher total tremor scores (p < 0.001), were older (p = 0.003), and had tremor of longer duration (p = 0.01). In logistic regression models, the odds of cranial tremor in a relative were not related to occurrence of cranial tremor in the proband (p > 0.24). CONCLUSIONS: Cranial tremor did not aggregate in families with ET; the major predictor of this disease feature was tremor severity rather than presence of cranial tremor in another family member.

Predicting age of onset in familial essential tremor: how much does age of onset run in families?

BACKGROUND: The extent to which age of onset of essential tremor (ET) aggregates in families is unknown; hence, it is unclear whether information about the age of onset in one family member can be used to predict the age of onset in others. METHODS: ET probands and relatives were enrolled in a genetic study at Columbia University. RESULTS: Data from 26 probands and 52 relatives were analyzed. The probands' age of onset correlated significantly with their relatives' age of onset (r = 0.50, p = 0.001). In 57.7% of cases, the relative's age of onset was within 10 years of the proband's onset (i.e. a 20-year age range). The proportion of affected relatives with age at onset <20 years was 64.7% in the families of probands with onset younger than 20 years, but only 7.7% in the families of probands with onset ≥20 years (p < 0.001). There was little evidence for genetic anticipation; 9/18 (50.0%) children reported a younger age of onset than the proband. CONCLUSIONS: In families containing multiple individuals with ET, the age at onset of probands and relatives was significantly correlated. Age of onset may be most tightly linked in families in which the proband had a young age of onset.

Polyamine pathway contributes to the pathogenesis of Parkinson disease.

The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.

Lack of association between cancer history and PARKIN genotype: a family based study in PARKIN/Parkinson's families.

A number of publications have attributed a tumor suppressive (TS) function to PARKIN, a gene associated with recessive familial early onset Parkinson's disease (EOPD). Discoveries of PARKIN deletions and point mutations in tumors, functional studies, and data from mouse models have been presented to support the hypothesis. We have asked whether PARKIN mutations are associated with history of cancer in humans. We interviewed 431 participants who were screened for PARKIN mutations, including 149 EOPD cases and their family members, who were unaware of mutation status. We found no significant difference in self-reported history of cancer among carriers of one or two PARKIN mutations and noncarriers, odds ratio 0.75 (95% confidence interval 0.27-1.83). In particular, no increase in cancer history was seen among homozygous and compound heterozygous mutation carriers compared to noncarriers. Therefore, we hypothesize that published studies attributing TS capability to PARKIN merit further exploration and we present a reevaluation of these data with respect to patterns of mutation frequencies in normal and cancer cells. We conclude that although Parkin may exert a suppressive effect in mice, further studies are required prior to assigning a TS function to PARKIN in humans.

SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk.

OBJECTIVE: Sorting mechanisms that cause the amyloid precursor protein (APP) and the ß-secretases and γ-secretases to colocalize in the same compartment play an important role in the regulation of Aß production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Aß. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD. METHODS: We analyzed the genetic associations between AD and 16 SORCS1-single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aß generation. RESULTS: Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ-secretase activity and Aß levels, the suppression of SorCS1 increased γ-secretase processing of APP and the levels of Aß. INTERPRETATIONS: These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD.