ArticleOncotarget2017
KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 47 citations in OpenAlex.
- Plasma alpha-synuclein levels in patients with Parkinson's disease: a systematic review and meta-analysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2019Pooled it
- Fragment-Based Discovery of KLK6 and KLK7 Inhibitors.Journal of chemical information and modeling · 2026Article
- A protein-small molecule conjugate as a bispecific inhibitor of proteases implicated in cancer metastasis.Scientific reports · 2026Article
- The expanding role of protease therapeutics (2012-2026): from replacement therapies to immune system modulation and beyond.The Biochemical journal · 2026Review
- Article
- HSP90α and KLK6 Co-Regulate Stress-Induced Prostate Cancer Cell Motility.bioRxiv : the preprint server for biology · 2025Article
- Proteolytic activities of extracellular vesicles attenuate A-synuclein aggregation.NPJ Parkinson's disease · 2025Article
- Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease.Cell reports · 2025Article
- Kallikrein-Related Peptidase 6 Contributes to Murine Intestinal Tumorigenesis Driven by a MutantCancers · 2024Article
- Assessing the performance of docking, FEP, and MM/GBSA methods on a series of KLK6 inhibitors.Journal of computer-aided molecular design · 2023Article
- Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.Pharmaceutics · 2023Review
- Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define putative diagnostic biosignatures for Parkinson's disease.Communications medicine · 2023Article
- Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration.Aging cell · 2022Review
- Activity-Based Probes for Proteases Pave the Way to Theranostic Applications.Pharmaceutics · 2022Review
- Article
- Bioengineered models of Parkinson's disease using patient-derived dopaminergic neurons exhibit distinct biological profiles in a 3D microenvironment.Cellular and molecular life sciences : CMLS · 2022Article
- The Role of Extracellular Matrix Components in the Spreading of Pathological Protein Aggregates.Frontiers in cellular neuroscience · 2022Review
- Comprehensive expression analysis with cell-type-specific transcriptome in ALS-linked mutant SOD1 mice: Revisiting the active role of glial cells in disease.Frontiers in cellular neuroscience · 2022Article
- Thyroarytenoid Muscle Gene Expression in a Rat Model of Early-Onset Parkinson's Disease.The Laryngoscope · 2021Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with α-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular α-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinant and naturally secreted KLK6 can readily cleave α-synuclein fibrils that have the potential for cell-to-cell propagation in "a prion-like mechanism". Importantly, KLK6-deficient primary cortical neurons have increased ability for α-synuclein fibril uptake. We also demonstrate that KLK6 activates proMMP2, which in turn can cleave α-synuclein. The repertoire of proteases activated by KLK6 in a neuronal environment was analyzed by degradomic profiling, which also identified ADAMTS19 and showed that KLK6 has a limited number of substrates indicating specific biological functions such as the regulation of α-synuclein turnover. We generated adenoviral vectors for KLK6 delivery and demonstrated that the levels of extracellular α-synuclein can be reduced by neuronally secreted KLK6. Our findings open the possibility to exploit KLK6 as a novel therapeutic target for Parkinson disease and other synucleinopathies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.