Publications by authors named "Jennifer A Ruskey"

Article Synopsis
  • - Variants in the CTSB gene are linked to an increased risk of Parkinson's disease (PD) and affect the activity of cathepsin B, an enzyme involved in breaking down proteins and regulating cellular processes related to autophagy and lysosome function.
  • - CatB can both degrade the harmful alpha-synuclein protein associated with PD and potentially create shorter versions of it that are more prone to aggregation, complicating its role in PD pathology.
  • - Experiments showed that inhibiting catB disrupts autophagy and lysosomal function, leading to an accumulation of toxic protein aggregates, while activating catB enhances the clearance of these aggregates in cell and neuron models.
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Previous studies have established that rare biallelic SYNJ1 mutations cause autosomal recessive parkinsonism and Parkinson's disease (PD). We analyzed 8165 PD cases, 818 early-onset-PD (EOPD, < 50 years) and 70,363 controls. Burden meta-analysis revealed an association between rare nonsynonymous variants and variants with high Combined Annotation-Dependent Depletion score (> 20) in the Sac1 SYNJ1 domain and PD (Pfdr = 0.

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Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2.

Objectives: Our goal was to investigate the effects of genetic variants on risk and time to LID.

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Article Synopsis
  • Variants in the GBA gene, which codes for glucocerebrosidase (GCase), are major genetic risk factors for Parkinson's disease (PD), leading to decreased GCase activity.
  • A genome-wide association study was conducted using two cohorts to identify common variants related to GCase activity, confirming known variants and discovering a new link involving the GAA gene, which encodes for acid alpha-glucosidase.
  • The identified associations suggest that other PD-risk loci may also influence GCase activity, indicating a need for further studies to explore these relationships and their functional implications.
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Previous studies have suggested that rare biallelic mutations may cause autosomal recessive parkinsonism and Parkinson's disease (PD). Our study explored the impact of rare variants in non-familial settings, including 8,165 PD cases, 818 early-onset PD (EOPD, <50 years) and 70,363 controls. Burden meta-analysis using optimized sequence Kernel association test (SKAT-O) revealed an association between rare nonsynonymous variants in the Sac1 SYNJ1 domain and PD (P=0.

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Background: Variants in the gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis.

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Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including and .

Objectives: To investigate the effects of genetic variants on risk and time to LID.

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Article Synopsis
  • A study investigated the relationship between the human leukocyte antigen (HLA) locus and synucleinopathies, specifically Lewy body dementia (LBD) and isolated REM sleep behavior disorder (iRBD), which are linked to neuroinflammation.
  • It was found that the HLA-DRB1*11:01 allele was significantly associated with iRBD, while several other alleles showed varying associations.
  • The results imply that the HLA locus may have distinct roles depending on the type of synucleinopathy being examined.
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Background: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear.

Objectives: To study rare ARSA variants in PD.

Methods: To study rare ARSA variants (minor allele frequency < 0.

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NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results.

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Background: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and , which encodes for the enzyme arylsulfatase A, remains controversial.

Objectives: To evaluate the association between rare variants and PD.

Methods: To study possible association of rare variants (minor allele frequency<0.

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Article Synopsis
  • - The study investigates the role of the human leukocyte antigen (HLA) locus in isolated REM sleep behavior disorder (iRBD), Lewy body dementia (LBD), and Parkinson's disease (PD), highlighting the genetic and neuroinflammatory links between these synucleinopathies.
  • - Researchers performed genetic analyses using data from over 1,000 iRBD patients and 2,600 LBD patients to identify associations between specific HLA alleles and disease susceptibility, finding strong links for certain alleles in iRBD but not in LBD.
  • - The results indicate a unique association of the HLA allele *11:01 with iRBD, suggesting that the genetic factors may differ between these
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Article Synopsis
  • * A genome-wide association study identified five genetic risk loci for RBD near specific genes (SNCA, GBA, TMEM175, INPP5F, and SCARB2), suggesting a genetic basis for the disorder.
  • * Further analysis indicates that certain genes, like SNCA-AS1, show different expression levels in various brain regions affected by RBD, paving the way for recognizing RBD as a distinct subtype of alpha-synucleinopathy for potential early interventions.
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The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway.

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Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy.

Objective: To examine the role of PSAP mutations in iRBD.

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We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson's disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes-11V, 13H, and 33H (OR = 0.

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Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry.

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The LRRK2 p.G2019S Parkinson's disease (PD) variant is associated with elevated glucocerebrosidase (GCase) activity in peripheral blood. We aimed to evaluate the association of other LRRK2 variants with PD and its association with GCase activity.

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Cognitive impairments are prevalent in Parkinson's disease (PD), but the underlying mechanisms of their development are unknown. In this study, we aimed to predict global cognition (GC) in PD with machine learning (ML) using structural neuroimaging, genetics and clinical and demographic characteristics. As a post-hoc analysis, we aimed to explore the connection between novel selected features and GC more precisely and to investigate whether this relationship is specific to GC or is driven by specific cognitive domains.

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Background: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP).

Objectives: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP.

Methods: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals.

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Neuropsychiatric symptoms (NPS) are common in Parkinson's disease (PD) and have demonstrated an association with the p. Val66Met, a polymorphism in the gene. Mild behavioral impairment (MBI) is a validated syndrome describing emergent and persistent NPS in older adults as a marker of potential cognitive decline and dementia.

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Objective: The objective of this study was to identify genetic variants on the X-chromosome associated with Parkinson disease (PD) risk.

Methods: We performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample.

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Objective: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD).

Methods: We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests.

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