Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches
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Following Alzheimer's, Parkinson's disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy is available. PD is tightly associated with alpha-synuclein (alpha-Syn) deposits, which become organised into insoluble, amyloid fibrils. As a typical intrinsically disordered protein, alpha-Syn adopts a monomeric, random coil conformation in an aqueous solution, while its interaction with lipid membranes drives the transition of the molecule part into an alpha-helical structure. The central unstructured region of alpha-Syn is involved in fibril formation by converting to well-defined, beta-sheet rich secondary structures. Presently, most therapeutic strategies against PD are focused on designing small molecules, peptides, and peptidomimetics that can directly target alpha-Syn and its aggregation pathway. Other approaches include gene silencing, c...ell transplantation, stimulation of intracellular clearance with autophagy promoters, and degradation pathways based on immunotherapy of amyloid fibrils. In the present review, we summarise the current advances related to alpha-Syn aggregation/neurotoxicity. These findings present a valuable arsenal for the further development of efficient, nontoxic, and non-invasive therapeutic protocols for disease-modifying therapy that tackles disease onset and progression in the future.
Keywords:
synucleinopathies / structure/function relationship / rationally designed peptidomimetics / protein misfolding / intrinsically disordered proteins / high throughput anti-aggregation drug screening / disaggregators / alpha-synuclein oligomers and fibrilsSource:
Cells, 2022, 11, 11Publisher:
- MDPI, Basel
Funding / projects:
- LEAPSyn-SCI - Late Embryogenesis Abundant Proteins: Structural Characterisation and Interaction With Α-Synuclein (RS-ScienceFundRS-Promis-6039663)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200042 (University of Belgrade, Institute of Molecular Genetics and Genetic Engineering) (RS-MESTD-inst-2020-200042)
- Science Fund, RS (PROMIS project LEAPSyn-SCI) [6039663]
- Singidunum University, Belgrade, RS
DOI: 10.3390/cells11111732
ISSN: 2073-4409
PubMed: 35681426
WoS: 000808857000001
Scopus: 2-s2.0-85130801409
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Vidović, Marija AU - Rikalović, Milena G. PY - 2022 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1598 AB - Following Alzheimer's, Parkinson's disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy is available. PD is tightly associated with alpha-synuclein (alpha-Syn) deposits, which become organised into insoluble, amyloid fibrils. As a typical intrinsically disordered protein, alpha-Syn adopts a monomeric, random coil conformation in an aqueous solution, while its interaction with lipid membranes drives the transition of the molecule part into an alpha-helical structure. The central unstructured region of alpha-Syn is involved in fibril formation by converting to well-defined, beta-sheet rich secondary structures. Presently, most therapeutic strategies against PD are focused on designing small molecules, peptides, and peptidomimetics that can directly target alpha-Syn and its aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation of intracellular clearance with autophagy promoters, and degradation pathways based on immunotherapy of amyloid fibrils. In the present review, we summarise the current advances related to alpha-Syn aggregation/neurotoxicity. These findings present a valuable arsenal for the further development of efficient, nontoxic, and non-invasive therapeutic protocols for disease-modifying therapy that tackles disease onset and progression in the future. PB - MDPI, Basel T2 - Cells T1 - Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches IS - 11 VL - 11 DO - 10.3390/cells11111732 ER -
@article{ author = "Vidović, Marija and Rikalović, Milena G.", year = "2022", abstract = "Following Alzheimer's, Parkinson's disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy is available. PD is tightly associated with alpha-synuclein (alpha-Syn) deposits, which become organised into insoluble, amyloid fibrils. As a typical intrinsically disordered protein, alpha-Syn adopts a monomeric, random coil conformation in an aqueous solution, while its interaction with lipid membranes drives the transition of the molecule part into an alpha-helical structure. The central unstructured region of alpha-Syn is involved in fibril formation by converting to well-defined, beta-sheet rich secondary structures. Presently, most therapeutic strategies against PD are focused on designing small molecules, peptides, and peptidomimetics that can directly target alpha-Syn and its aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation of intracellular clearance with autophagy promoters, and degradation pathways based on immunotherapy of amyloid fibrils. In the present review, we summarise the current advances related to alpha-Syn aggregation/neurotoxicity. These findings present a valuable arsenal for the further development of efficient, nontoxic, and non-invasive therapeutic protocols for disease-modifying therapy that tackles disease onset and progression in the future.", publisher = "MDPI, Basel", journal = "Cells", title = "Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches", number = "11", volume = "11", doi = "10.3390/cells11111732" }
Vidović, M.,& Rikalović, M. G.. (2022). Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches. in Cells MDPI, Basel., 11(11). https://doi.org/10.3390/cells11111732
Vidović M, Rikalović MG. Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches. in Cells. 2022;11(11). doi:10.3390/cells11111732 .
Vidović, Marija, Rikalović, Milena G., "Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches" in Cells, 11, no. 11 (2022), https://doi.org/10.3390/cells11111732 . .