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| Status |
Public on Feb 17, 2025 |
| Title |
Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson’s disease |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson’s disease and forms inclusions in neurons called Lewy Bodies. While the mechanism underlying the dysregulation of αSyn in Parkinson’s disease is unclear, it is thought that prionoid cell-to-cell propagation of αSyn has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates αSyn propagation. Follow up experiments were undertaken for two of those genes, TAX1BP1 and ADAMTS19, to study the mechanism with which they regulate αSyn homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) “3k” αSyn under doxycycline induction. 3k αSyn spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed that TAX1BP1 and ADAMTS19 regulate how αSyn interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinson’s disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down of TAX1BP1 or ADAMTS19. Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinson’s disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of αSyn pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinson’s disease: increased burden of risk variants across genetic networks dysregulates pathways underlying αSyn homeostasis, thereby leading to pathology and neurodegeneration.
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| Overall design |
We determined which genes are differentially expressed after knocking down two genes of interest, TAX1BP1 or ADAMTS19, in comparison to scrambled (non-targeting) control. Three biological (independent) replicates were completed for this experiment.
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| Contributor(s) |
Eleanna K |
| Citation missing |
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| Submission date |
Aug 29, 2024 |
| Last update date |
Feb 17, 2025 |
| Contact name |
Eleanna Kara |
| E-mail(s) |
ek851@rwjms.rutgers.edu
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| Organization name |
Rutgers University
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| Street address |
683 Hoes Lane West
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| City |
Piscataway |
| State/province |
New Jersey |
| ZIP/Postal code |
08901 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (9)
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| GSM8489846 |
3K M17D cells, transfection with siRNA against ADAMTS19, day 2 post-transfection, biological replicate 1 |
| GSM8489847 |
3K M17D cells, transfection with siRNA against ADAMTS19, day 2 post-transfection, biological replicate 2 |
| GSM8489848 |
3K M17D cells, transfection with siRNA against ADAMTS19, day 2 post-transfection, biological replicate 3 |
| GSM8489849 |
3K M17D cells, transfection with scrambled siRNA, day 2 post-transfection, biological replicate 1 |
| GSM8489850 |
3K M17D cells, transfection with scrambled siRNA, day 2 post-transfection, biological replicate 2 |
| GSM8489851 |
3K M17D cells, transfection with scrambled siRNA, day 2 post-transfection, biological replicate 3 |
| GSM8489852 |
3K M17D cells, transfection with siRNA against TAX1BP1, day 2 post-transfection, biological replicate 1 |
| GSM8489853 |
3K M17D cells, transfection with siRNA against TAX1BP1, day 2 post-transfection, biological replicate 2 |
| GSM8489854 |
3K M17D cells, transfection with siRNA against TAX1BP1, day 2 post-transfection, biological replicate 3 |
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| Relations |
| BioProject |
PRJNA1154386 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE276032_TPM_values_SCR_TAX1BP1_ADAMTS19.csv.gz |
1.3 Mb |
(ftp)(http) |
CSV |
| GSE276032_raw_counts_SCR_TAX1BP1_ADAMTS19.csv.gz |
885.2 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
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