There are many active research projects accessing and applying shared ADNI data. Use the search above to find specific research focuses on the active ADNI investigations. This information is requested annually as a requirement for data access.
| Principal Investigator | |
| Principal Investigator's Name: | Jiou Wang |
| Institution: | Johns Hopkins University Bloomberg School of Public Health |
| Department: | Biochemistry and Molecular Biology |
| Country: | |
| Proposed Analysis: | The most common pathologic feature of different forms of ALS/FTD is the proteinaceous inclusions positive for disease-associated proteins such as SOD1, TDP-43, FUS, ataxin 2, profilin 1, and C9orf72 poly-dipeptides. For instance, TDP-43-positive inclusions are the pathologic hallmark of ALS (~97% of cases) and FTD (~45% of cases). Another striking feature in many forms of ALS/FTD is their connection to the protein quality control systems, especially autophagy. There are a multitude of ALS/FTD genes with functions related to the autophagic system, including but not limited to p62, optineurin, VCP, ubiquilin 2, and TBK1. In the most common form of ALS/FTD linked to the hexanucleotide repeat expansion in the C9orf72 gene, the repeat-associated non-ATG-dependent translation produces toxic poly-dipeptide repeats, and C9orf72 itself functions in the autophagy-lysosome pathway. Protein homeostasis is fundamental to the functioning of all living cells. Perturbation of the homeostasis, or proteotoxicity, plays an important role in the pathogenesis of ALS and related neurodegenerative diseases. To guard against proteotoxicity, cells have evolved sophisticated quality control mechanisms that make adaptations including enhanced turnover of misfolded proteins. However, how the quality control systems are coordinated through higher-order regulatory pathways is not fully understood. Through an unbiased screen, we have discovered a unique suppressor of proteotoxicity, the ubiquitin-specific protease USP7, whose action is conserved from invertebrate to mammalian systems and mediated by the TGFβ-SMAD pathway. Specifically, USP7 acts on protein quality control through the SMAD2 transcription modulator of the TGFβ pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. USP7 acts as a regulatory switch that significantly influences the clearance of misfolded proteins such as mutant SOD1 and TDP-43. In addition, we found that the SMAD2 protein level is dysregulated in ALS patients’ tissues from the central nervous system. Together with the reports that TGFβ ligands were dysregulated in ALS patients’ tissues, our findings suggest that the SMAD2-related protein quality control network is impaired in ALS-associated neurodegeneration. These findings reveal a previously unknown regulatory pathway for protein quality control implicated in ALS and proteotoxicity-related neurodegeneration. Given that TGFβ ligands have been reported to show protective activity in mammalian models of Alzheimer’s and Parkinson’s diseases, it is possible that the SMAD2-related protein quality control network is widely implicated in the pathogenesis of proteotoxicity-associated neurodegeneration. Importantly, altered concentrations of TGFβ in the CSF has been associated with several neurological diseases including Alzheimer’s disease and schizophrenia. These facts suggest that problems with TGFβ signaling may be particularly relevant to proteotoxicity-related neurodegeneration in ALS and FTD and offer an opportunity to identify biomarkers that could serve as the disease signature or be used to monitor TGFβ signaling functions during disease progression or therapeutic tests. We will employ transcriptomic methods to identify changes in the expression of genes regulated by the TGFβ-SMAD pathway, especially the downstream of SMAD2. In preliminary studies, we analyzed the spinal cords by western blotting for >24 ALS patients, we found that compared to non-ALS controls the level of SMAD2 protein was consistently elevated in both familial and sporadic ALS patients. Among the ALS patients tested, a majority of cases were documented harboring the TDP-43 proteinaceous inclusion pathology and some carrying the C9ORF72 repeat expansion mutations. These data are consistent with previous reports that TGFβ is upregulated in ALS patients’ tissues. We will perform the transcriptomic studies using brain/spinal cord tissues from C9-ALS/FTD patients to identify specific gene expression changes as a result of the perturbed TGFβ-SMAD signaling. In parallel, we will apply proteomic approaches to determine the molecular changes at the protein level that are dysregulated in patients’ tissues. Using the CSF databases, we hope to map the molecular signature of altered TGFβ-SMAD signaling in neurodegeneration in order to identify the candidate biomarkers that we could further test and validate in patients’ CSF samples. |
| Additional Investigators |
