Skip to content
2000
image of Novel Therapeutic Strategies in Targeting Alpha Synuclein Dysfunction Pathways for Parkinson’s Disease Treatment

Abstract

Parkinson’s disease (PD) is a neurodegenerative, progressive disorder presenting with both motor and non-motor symptoms. Its pathogenesis likely results from dysfunction of the presynaptic protein alpha-synuclein, which produces neuronal toxicity and aggregation in Lewy bodies. Relevant literature was identified through systematic searches in PubMed, Scopus, Web of Science, and Google Scholar using a range of descriptors in English. In this review, we investigated novel therapeutic strategies targeting alpha-synuclein, including small molecule inhibitors, immunotherapies, RNA-based therapies, and protein clearance mechanisms. It also reviews our recent advances in nanotechnological development for drug delivery systems to enhance therapeutic efficacy using lipid-based nanoparticles, polymeric carriers, and exosome delivery. Although much progress has been achieved, including clinical translation, biomarker development, and large-scale production, many challenges still remain. With the help of emerging trends such as AI-driven nanotechnology and personalized medicine, these gaps can be targeted. We emphasize the importance of integrated and multi-targeted approaches for the development of effective disease-modifying therapies for PD.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/dmb/10.2174/0118723128397400250910222116
2025-10-14
2026-01-05

  • From This Site

    /content/journals/dmb/10.2174/0118723128397400250910222116
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Bloem B.R. Okun M.S. Klein C. Parkinson’s disease. Lancet 2021 397 10291 2284 2303 10.1016/S0140‑6736(21)00218‑X 33848468
    [Google Scholar]
  2. Chen W. Xu Z.M. Wang G. Chen S.D. Non-motor symptoms of Parkinson’s disease in China: A review of the literature. Parkinsonism Relat. Disord. 2012 18 5 446 452 10.1016/j.parkreldis.2012.02.002 22425544
    [Google Scholar]
  3. Bernal-Conde L.D. Ramos-Acevedo R. Reyes-Hernández M.A. Balbuena-Olvera A.J. Morales-Moreno I.D. Argüero-Sánchez R. Schüle B. Guerra-Crespo M. Alpha-synuclein physiology and pathology: A perspective on cellular structures and organelles. Front. Neurosci. 2020 13 1399 10.3389/fnins.2019.01399 32038126
    [Google Scholar]
  4. Du X. Xie X. Liu R. The role of α-synuclein oligomers in Parkinson’s disease. Int. J. Mol. Sci. 2020 21 22 8645 10.3390/ijms21228645 33212758
    [Google Scholar]
  5. Woitalla D. Buhmann C. Hilker-Roggendorf R. Höglinger G. Koschel J. Müller T. Weise D. Role of dopamine agonists in Parkinson’s disease therapy. J. Neural Transm. (Vienna) 2023 130 6 863 873 10.1007/s00702‑023‑02647‑0 37165120
    [Google Scholar]
  6. Oliveira L.M.A. Gasser T. Edwards R. Zweckstetter M. Melki R. Stefanis L. Lashuel H.A. Sulzer D. Vekrellis K. Halliday G.M. Tomlinson J.J. Schlossmacher M. Jensen P.H. Schulze-Hentrich J. Riess O. Hirst W.D. El-Agnaf O. Mollenhauer B. Lansbury P. Outeiro T.F. Alpha-synuclein research: Defining strategic moves in the battle against Parkinson’s disease. NPJ Parkinsons Dis. 2021 7 1 65 10.1038/s41531‑021‑00203‑9 34312398
    [Google Scholar]
  7. Ekhator C. Qureshi M.Q. Zuberi A.W. Hussain M. Sangroula N. Yerra S. Devi M. Naseem M.A. Bellegarde S.B. Pendyala P.R. Advances and opportunities in nanoparticle drug delivery for central nervous system disorders: A review of current advances. Cureus 2023 15 8 e44302 10.7759/cureus.44302 37649926
    [Google Scholar]
  8. Sulzer D. Edwards R.H. The physiological role of α‐synuclein and its relationship to Parkinson’s Disease. J. Neurochem. 2019 150 5 475 486 10.1111/jnc.14810 31269263
    [Google Scholar]
  9. Yaribash S. Mohammadi K. Sani M.A. Alpha-synuclein pathophysiology in neurodegenerative disorders: A review focusing on molecular mechanisms and treatment advances in Parkinson’s disease. Cell. Mol. Neurobiol. 2025 45 1 30 10.1007/s10571‑025‑01544‑2 40140103
    [Google Scholar]
  10. Morales-Martínez A. Martínez-Gómez P.A. Martinez-Fong D. Villegas-Rojas M.M. Pérez-Severiano F. Del Toro-Colín M.A. Delgado-Minjares K.M. Blanco-Alvarez V.M. Leon-Chavez B.A. Aparicio-Trejo O.E. Baéz-Cortés M.T. Cardenas-Aguayo M.C. Luna-Muñoz J. Pacheco-Herrero M. Angeles-López Q.D. Martínez-Dávila I.A. Salinas-Lara C. Romero-López J.P. Sánchez-Garibay C. Méndez-Cruz A.R. Soto-Rojas L.O. Oxidative stress and mitochondrial complex I dysfunction correlate with neurodegeneration in an α-synucleinopathy animal model. Int. J. Mol. Sci. 2022 23 19 11394 10.3390/ijms231911394 36232716
    [Google Scholar]
  11. Burré J. Sharma M. Südhof T.C. Cell biology and pathophysiology of α-synuclein. Cold Spring Harb. Perspect. Med. 2018 8 3 a024091 10.1101/cshperspect.a024091 28108534
    [Google Scholar]
  12. Rocha E.M. De Miranda B. Sanders L.H. Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson's disease Neurobiol. Dis 2018 109 Pt B 249 257 10.1016/j.nbd.2017.04.004 28400134
    [Google Scholar]
  13. Calo L. Wegrzynowicz M. Santivañez-Perez J. Grazia Spillantini M. Synaptic failure and α‐synuclein. Mov. Disord. 2016 31 2 169 177 10.1002/mds.26479 26790375
    [Google Scholar]
  14. Ghosh D. Mehra S. Sahay S. Singh P.K. Maji S.K. α-synuclein aggregation and its modulation. Int. J. Biol. Macromol. 2017 100 37 54 10.1016/j.ijbiomac.2016.10.021 27737778
    [Google Scholar]
  15. Xia Y. Zhang G. Han C. Ma K. Guo X. Wan F. Kou L. Yin S. Liu L. Huang J. Xiong N. Wang T. Microglia as modulators of exosomal alpha-synuclein transmission. Cell Death Dis. 2019 10 3 174 10.1038/s41419‑019‑1404‑9 30787269
    [Google Scholar]
  16. Neupane S. De Cecco E. Aguzzi A. The hidden cell-to-cell trail of α-synuclein aggregates. J. Mol. Biol. 2023 435 12 167930 10.1016/j.jmb.2022.167930 36566800
    [Google Scholar]
  17. Bridi J.C. Hirth F. Mechanisms of α-synuclein induced synaptopathy in Parkinson’s disease. Front. Neurosci. 2018 12 80 10.3389/fnins.2018.00080 29515354
    [Google Scholar]
  18. Lin K.J. Lin K.L. Chen S.D. Liou C.W. Chuang Y.C. Lin H.Y. Lin T.K. The overcrowded crossroads: Mitochondria, alpha-synuclein, and the endo-lysosomal system interaction in Parkinson’s disease. Int. J. Mol. Sci. 2019 20 21 5312 10.3390/ijms20215312 31731450
    [Google Scholar]
  19. Ganjam G.K. Bolte K. Matschke L.A. Neitemeier S. Dolga A.M. Höllerhage M. Höglinger G.U. Adamczyk A. Decher N. Oertel W.H. Culmsee C. Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons. Cell Death Dis. 2019 10 11 865 10.1038/s41419‑019‑2091‑2 31727879
    [Google Scholar]
  20. Zaltieri M. Longhena F. Pizzi M. Missale C. Spano P. Bellucci A. Mitochondrial dysfunction and α-synuclein synaptic pathology in Parkinson’s disease: Who’s on first? Parkinsons Dis. 2015 2015 1 1 10 10.1155/2015/108029 25918668
    [Google Scholar]
  21. Tóth G. Gardai S.J. Zago W. Bertoncini C.W. Cremades N. Roy S.L. Tambe M.A. Rochet J.C. Galvagnion C. Skibinski G. Finkbeiner S. Bova M. Regnstrom K. Chiou S.S. Johnston J. Callaway K. Anderson J.P. Jobling M.F. Buell A.K. Yednock T.A. Knowles T.P.J. Vendruscolo M. Christodoulou J. Dobson C.M. Schenk D. McConlogue L. Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson’s disease. PLoS One 2014 9 2 e87133 10.1371/journal.pone.0087133 24551051
    [Google Scholar]
  22. Vidović M. Rikalovic M.G. Alpha-synuclein aggregation pathway in Parkinson’s disease: Current status and novel therapeutic approaches. Cells 2022 11 11 1732 10.3390/cells11111732 35681426
    [Google Scholar]
  23. Sechi G.P. Sechi M.M. Small molecules, α-synuclein pathology, and the search for effective treatments in Parkinson’s disease. Int. J. Mol. Sci. 2024 25 20 11198 10.3390/ijms252011198 39456980
    [Google Scholar]
  24. Jankovic J. Tan E.K. Parkinson’s disease: Etiopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry 2020 91 8 795 808 10.1136/jnnp‑2019‑322338 32576618
    [Google Scholar]
  25. Crooke S.T. Baker B.F. Crooke R.M. Liang X. Antisense technology: An overview and prospectus. Nat. Rev. Drug Discov. 2021 20 6 427 453 10.1038/s41573‑021‑00162‑z 33762737
    [Google Scholar]
  26. Li D. Aung-Htut M.T. Ham K.A. Fletcher S. Wilton S.D. A splice intervention therapy for autosomal recessive juvenile Parkinson’s disease arising from Parkin mutations. Int. J. Mol. Sci. 2020 21 19 7282 10.3390/ijms21197282 33019779
    [Google Scholar]
  27. Zhang K. Zhu S. Li J. Jiang T. Feng L. Pei J. Wang G. Ouyang L. Liu B. Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson’s disease. Acta Pharm. Sin. B 2021 11 10 3015 3034 10.1016/j.apsb.2021.02.016 34729301
    [Google Scholar]
  28. Menzies F.M. Fleming A. Rubinsztein D.C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 2015 16 6 345 357 10.1038/nrn3961 25991442
    [Google Scholar]
  29. Morato Torres C.A. Wassouf Z. Zafar F. Sastre D. Outeiro T.F. Schüle B. The role of alpha-synuclein and other Parkinson’s genes in neurodevelopmental and neurodegenerative disorders. Int. J. Mol. Sci. 2020 21 16 5724 10.3390/ijms21165724 32785033
    [Google Scholar]
  30. Pérez-Arancibia R. Cisternas-Olmedo M. Sepúlveda D. Troncoso-Escudero P. Vidal R.L. Small molecules to perform big roles: The search for Parkinson’s and Huntington’s disease therapeutics. Front. Neurosci. 2023 16 1084493 10.3389/fnins.2022.1084493 36699535
    [Google Scholar]
  31. Savitt D. Jankovic J. Targeting alpha-synuclein in Parkinson’s disease: Progress towards the development of disease-modifying therapeutics. Drugs 2019 79 8 797 810 10.1007/s40265‑019‑01104‑1 30982161
    [Google Scholar]
  32. Robustelli P. Ibanez-de-Opakua A. Campbell-Bezat C. Giordanetto F. Becker S. Zweckstetter M. Pan A.C. Shaw D.E. Molecular basis of small-molecule binding to α-synuclein. J. Am. Chem. Soc. 2022 144 6 2501 2510 10.1021/jacs.1c07591 35130691
    [Google Scholar]
  33. Auluck P.K. Caraveo G. Lindquist S. α-Synuclein: Membrane interactions and toxicity in Parkinson’s disease. Annu. Rev. Cell Dev. Biol. 2010 26 1 211 233 10.1146/annurev.cellbio.042308.113313 20500090
    [Google Scholar]
  34. Chiti F. Dobson C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 2006 75 1 333 366 10.1146/annurev.biochem.75.101304.123901 16756495
    [Google Scholar]
  35. Baggett D. Olson A. Parmar M.S. Novel approaches targeting α-Synuclein for Parkinson’s Disease: Current progress and future directions for the disease-modifying therapies. Brain Disord. 2024 16 100163 10.1016/j.dscb.2024.100163
    [Google Scholar]
  36. Panicker N. Saminathan H. Jin H. Neal M. Harischandra D.S. Gordon R. Kanthasamy K. Lawana V. Sarkar S. Luo J. Anantharam V. Kanthasamy A.G. Kanthasamy A. Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson’s disease. J. Neurosci. 2015 35 27 10058 10077 10.1523/JNEUROSCI.0302‑15.2015 26157004
    [Google Scholar]
  37. Olanow C.W. Brundin P. Parkinson’s disease and alpha synuclein: Is Parkinson’s disease a prion-like disorder? Mov. Disord. 2013 28 1 31 40 10.1002/mds.25373 23390095
    [Google Scholar]
  38. Peña-Díaz S. García-Pardo J. Ventura S. Development of small molecules targeting α-synuclein aggregation: A promising strategy to treat Parkinson’s disease. Pharmaceutics 2023 15 3 839 10.3390/pharmaceutics15030839 36986700
    [Google Scholar]
  39. Bendor J.T. Logan T.P. Edwards R.H. The Function of α-Synuclein. Neuron 2013 79 6 1044 1066 10.1016/j.neuron.2013.09.004 24050397
    [Google Scholar]
  40. Cremades N. Chen S.W. Dobson C.M. Structural characteristics of alpha-synuclein oligomers. Int. Rev. Cell Mol. Biol. 2017 329 79 143 10.1016/bs.ircmb.2016.08.010 28109332
    [Google Scholar]
  41. Martinelli A.H.S. Lopes F.C. John E.B.O. Carlini C.R. Ligabue-Braun R. Modulation of disordered proteins with a focus on neurodegenerative diseases and other pathologies. Int. J. Mol. Sci. 2019 20 6 1322 10.3390/ijms20061322 30875980
    [Google Scholar]
  42. Goto A. Yamamoto S. Iwasaki S. Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: Advances, challenges, and future perspectives. Biopharm. Drug Dispos. 2023 44 1 26 47 10.1002/bdd.2338 36336817
    [Google Scholar]
  43. Kim B.S. Song J.A. Jang K.H. Jang T. Jung B. Yoo S.E. Lee J.M. Kim E. Pharmacological intervention targeting FAF1 restores autophagic flux for α-synuclein degradation in the brain of a Parkinson’s disease mouse model. ACS Chem. Neurosci. 2022 13 6 806 817 10.1021/acschemneuro.1c00828 35230076
    [Google Scholar]
  44. Jindal A. Mainuddin; Kumar, A.; Ratnesh, R.K.; Singh, J. Nanotechnology driven lipid and metalloid based formulations targeting blood-brain barrier (3b) for brain tumor. Indian J. Microbiol. 2025 65 1 92 119 10.1007/s12088‑024‑01330‑6 40371021
    [Google Scholar]
  45. Gabr M.T. Peccati F. Dual targeting of monomeric tau and α-synuclein aggregation: A new multitarget therapeutic strategy for neurodegeneration. ACS Chem. Neurosci. 2020 11 14 2051 2057 10.1021/acschemneuro.0c00281 32579329
    [Google Scholar]
  46. Allen S.G. Meade R.M. White Stenner L.L. Mason J.M. Peptide-based approaches to directly target alpha-synuclein in Parkinson’s disease. Mol. Neurodegener. 2023 18 1 80 10.1186/s13024‑023‑00675‑8 37940962
    [Google Scholar]
  47. Fields C.R. Bengoa-Vergniory N. Wade-Martins R. Targeting alpha-synuclein as a therapy for Parkinson’s disease. Front. Mol. Neurosci. 2019 12 299 10.3389/fnmol.2019.00299 31866823
    [Google Scholar]
  48. Lindestam Arlehamn C.S. Dhanwani R. Pham J. Kuan R. Frazier A. Rezende Dutra J. Phillips E. Mallal S. Roederer M. Marder K.S. Amara A.W. Standaert D.G. Goldman J.G. Litvan I. Peters B. Sulzer D. Sette A. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat. Commun. 2020 11 1 1875 10.1038/s41467‑020‑15626‑w 32313102
    [Google Scholar]
  49. Schwab A.D. Thurston M.J. Machhi J. Olson K.E. Namminga K.L. Gendelman H.E. Mosley R.L. Immunotherapy for Parkinson’s disease. Neurobiol. Dis. 2020 137 104760 10.1016/j.nbd.2020.104760 31978602
    [Google Scholar]
  50. Reynolds A.D. Banerjee R. Liu J. Gendelman H.E. Lee Mosley R. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J. Leukoc. Biol. 2007 82 5 1083 1094 10.1189/jlb.0507296 17675560
    [Google Scholar]
  51. Mosley R.L. Gendelman H.E. T regulatory cells and neurodegeneration: Loss of restraint? J. Neuroimmune Pharmacol. 2017 12 4 712 727
    [Google Scholar]
  52. George S. Brundin P. Immunotherapy in Parkinson’s disease: Micromanaging alpha-synuclein aggregation. J. Parkinsons Dis. 2015 5 3 413 424 10.3233/JPD‑150630 26406122
    [Google Scholar]
  53. Masliah E. Rockenstein E. Mante M. Crews L. Spencer B. Adame A. Patrick C. Trejo M. Ubhi K. Rohn T.T. Mueller-Steiner S. Seubert P. Barbour R. McConlogue L. Buttini M. Games D. Schenk D. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One 2011 6 4 e19338 10.1371/journal.pone.0019338 21559417
    [Google Scholar]
  54. Bae E.J. Lee H.J. Rockenstein E. Ho D.H. Park E.B. Yang N.Y. Desplats P. Masliah E. Lee S.J. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci. 2012 32 39 13454 13469 10.1523/JNEUROSCI.1292‑12.2012 23015436
    [Google Scholar]
  55. Wang Z. Gao G. Duan C. Yang H. Progress of immunotherapy of anti-α-synuclein in Parkinson’s disease. Biomed. Pharmacother. 2019 115 108843 10.1016/j.biopha.2019.108843 31055236
    [Google Scholar]
  56. Schenk D.B. Koller M. Ness D.K. Griffith S.G. Grundman M. Zago W. Soto J. Atiee G. Ostrowitzki S. Kinney G.G. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov. Disord. 2017 32 2 211 218 10.1002/mds.26878 27886407
    [Google Scholar]
  57. Shahaduzzaman M. Nash K.R. Hudson C. Sharif M. Grimmig B. Lin W.C. Anti-α-synuclein single chain antibody blocks uptake and propagation of misfolded α-synuclein and improves motor function in Parkinson’s disease mouse model. Neurobiol. Aging 2015 36 9 2226 2240
    [Google Scholar]
  58. Fleming S.M. Davis A. Simons E. Targeting alpha-synuclein via the immune system in Parkinson’s disease: Current vaccine therapies. Neuropharmacology 2022 202 108870 10.1016/j.neuropharm.2021.108870 34742741
    [Google Scholar]
  59. Masliah E. Rockenstein E. Adame A. Alford M. Crews L. Hashimoto M. Seubert P. Lee M. Goldstein J. Chilcote T. Games D. Schenk D. Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 2005 46 6 857 868 10.1016/j.neuron.2005.05.010 15953415
    [Google Scholar]
  60. Jankovic J. Goodman I. Safirstein B. Marmon T.K. Schenk D.B. Koller M. Zago W. Ness D.K. Griffith S.G. Grundman M. Soto J. Ostrowitzki S. Boess F.G. Martin-Facklam M. Quinn J.F. Isaacson S.H. Omidvar O. Ellenbogen A. Kinney G.G. Safety and tolerability of multiple ascending doses of PRX002, an anti–synuclein monoclonal antibody, in patients with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2018 75 10 1206 1214 10.1001/jamaneurol.2018.1487 29913017
    [Google Scholar]
  61. Caramiello A.M. Pirota V. Novel therapeutic horizons: SNCA targeting in Parkinson’s disease. Biomolecules 2024 14 8 949 10.3390/biom14080949 39199337
    [Google Scholar]
  62. Buttery P.C. Barker R.A. Gene and cell-based therapies for Parkinson’s disease: Where are we? Neurotherapeutics 2020 17 4 1539 1562 10.1007/s13311‑020‑00940‑4 33128174
    [Google Scholar]
  63. Palfi S. Gurruchaga J.M. Ralph G.S. Lepetit H. Lavisse S. Buttery P.C. Watts C. Miskin J. Kelleher M. Deeley S. Iwamuro H. Lefaucheur J.P. Thiriez C. Fenelon G. Lucas C. Brugières P. Gabriel I. Abhay K. Drouot X. Tani N. Kas A. Ghaleh B. Le Corvoisier P. Dolphin P. Breen D.P. Mason S. Guzman N.V. Mazarakis N.D. Radcliffe P.A. Harrop R. Kingsman S.M. Rascol O. Naylor S. Barker R.A. Hantraye P. Remy P. Cesaro P. Mitrophanous K.A. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: A dose escalation, open-label, phase 1/2 trial. Lancet 2014 383 9923 1138 1146 10.1016/S0140‑6736(13)61939‑X 24412048
    [Google Scholar]
  64. Christine C.W. Bankiewicz K.S. Van Laar A.D. Richardson R.M. Ravina B. Kells A.P. Boot B. Martin A.J. Nutt J. Thompson M.E. Larson P.S. Magnetic resonance imaging–guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease. Ann. Neurol. 2019 85 5 704 714 10.1002/ana.25450 30802998
    [Google Scholar]
  65. Pandey S.K. Singh R.K. Recent developments in nucleic acid-based therapies for Parkinson’s disease: Current status, clinical potential, and future strategies. Front. Pharmacol. 2022 13 986668 10.3389/fphar.2022.986668 36339626
    [Google Scholar]
  66. Teil M. Arotcarena M.L. Meletis K. AAV-shRNA targeting alpha-synuclein prevents neurodegeneration in a rat model of Parkinson’s disease. Mol. Ther. 2020 28 10 2311 2325
    [Google Scholar]
  67. Nakamori M. Junn E. Mochizuki H. Mouradian M.M. Nucleic acid-based therapeutics for Parkinson’s disease. Neurotherapeutics 2019 16 2 287 298 10.1007/s13311‑019‑00714‑7 30756362
    [Google Scholar]
  68. Shalaby K.E. El-Agnaf O.M.A. Gene-based therapeutics for Parkinson’s disease. Biomedicines 2022 10 8 1790 10.3390/biomedicines10081790 35892690
    [Google Scholar]
  69. Axelsen T.M. Woldbye D.P.D. Gene therapy for Parkinson’s disease, an update. J. Parkinsons Dis. 2018 8 2 195 215 10.3233/JPD‑181331 29710735
    [Google Scholar]
  70. Cole T.A. Zhao H. Collier T.J. Sandoval I. Sortwell C.E. Steece-Collier K. Daley B.F. Booms A. Lipton J. Welch M. Berman M. Jandreski L. Graham D. Weihofen A. Celano S. Schulz E. Cole-Strauss A. Luna E. Quach D. Mohan A. Bennett C.F. Swayze E.E. Kordasiewicz H.B. Luk K.C. Paumier K.L. α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease. JCI Insight 2021 6 5 e135633 10.1172/jci.insight.135633 33682798
    [Google Scholar]
  71. Szunyogh S. Carroll E. Wade-Martins R. Recent developments in gene therapy for Parkinson’s disease. Mol. Ther. 2025 33 5 2052 2064 10.1016/j.ymthe.2025.03.030 40121531
    [Google Scholar]
  72. Muramatsu S. The current status of gene therapy for Parkinson’s disease. Ann. Neurosci. 2010 17 2 92 95 10.5214/ans.0972‑7531.1017209 25205879
    [Google Scholar]
  73. Ridler C. Parkinson disease gene therapy rewires brain circuits to improve motor function. Nat. Rev. Neurol. 2019 15 1 2 10.1038/s41582‑018‑0120‑x 30542071
    [Google Scholar]
  74. Choi H.I. Kim T. Kim J.W. Lee G.J. Choi J. Chae Y.J. Kim E. Koo T.S. Rat pharmacokinetics and in vitro metabolite identification of KM-819, a Parkinson’s disease candidate, using LC-MS/MS and LC-HRMS. Molecules 2024 29 5 1004 10.3390/molecules29051004 38474516
    [Google Scholar]
  75. Yao T.X. Ayipo Y.O. Mordi M.N. In silico pharmacological evaluation of tetrahydro-β-carboline derivatives as putative inhibitors of alpha-synuclein and dopa decarboxylase for Parkinson’s disease. Trends Sci. 2023 20 11 6008 10.48048/tis.2023.6008
    [Google Scholar]
  76. Mittal K.R. Pharasi N. Sarna B. Singh M. Rachana; Haider, S.; Singh, S.K.; Dua, K.; Jha, S.K.; Dey, A.; Ojha, S.; Mani, S.; Jha, N.K. Nanotechnology-based drug delivery for the treatment of CNS disorders. Transl. Neurosci. 2022 13 1 527 546 10.1515/tnsci‑2022‑0258 36741545
    [Google Scholar]
  77. Liu Y. Liang Y. Yuhong J. Xin P. Han J.L. Du Y. Yu X. Zhu R. Zhang M. Chen W. Ma Y. Advances in nanotechnology for enhancing the solubility and bioavailability of poorly soluble drugs. Drug Des. Devel. Ther. 2024 18 1469 1495 10.2147/DDDT.S447496 38707615
    [Google Scholar]
  78. Amiri M. Jafari S. Kurd M. Mohamadpour H. Khayati M. Ghobadinezhad F. Tavallaei O. Derakhshankhah H. Sadegh Malvajerd S. Izadi Z. Engineered solid lipid nanoparticles and nanostructured lipid carriers as new generations of blood–brain barrier transmitters. ACS Chem. Neurosci. 2021 12 24 4475 4490 10.1021/acschemneuro.1c00540 34841846
    [Google Scholar]
  79. Menon S. Armstrong S. Hamzeh A. Visanji N.P. Sardi S.P. Tandon A. Alpha-synuclein targeting therapeutics for Parkinson’s disease and related synucleinopathies. Front. Neurol. 2022 13 852003 10.3389/fneur.2022.852003 35614915
    [Google Scholar]
  80. Linazasoro G. Potential applications of nanotechnologies to Parkinson’s disease therapy. Parkinsonism Relat. Disord. 2008 14 5 383 392 10.1016/j.parkreldis.2007.11.012 18329315
    [Google Scholar]
  81. Krsek A. Baticic L. Nanotechnology-driven therapeutic innovations in neurodegenerative disorders: A focus on Alzheimer’s and Parkinson’s disease. Future Pharmacol. 2024 4 2 352 379 10.3390/futurepharmacol4020020
    [Google Scholar]
  82. Moni M.M.R. Begum M.M. Uddin M.S. Ashraf G.M. Deciphering the role of nanoparticle-based treatment for Parkinson’s disease. Curr. Drug Metab. 2021 22 7 550 560 10.2174/1389200222666210202110129 33530903
    [Google Scholar]
  83. Baskin J. Jeon J.E. Lewis S.J.G. Nanoparticles for drug delivery in Parkinson’s disease. J. Neurol. 2021 268 5 1981 1994 10.1007/s00415‑020‑10291‑x 33141248
    [Google Scholar]
  84. Jayaraj R. Chandramohan V. Namasivayam E. Nanomedicine for Parkinson disease: Current status and future perspective. Int. J. Pharm. Bio Sci. 2013 4 692 e704
    [Google Scholar]
  85. Rahman M.M. Ferdous K.S. Ahmed M. Emerging promise of nanoparticle-based treatment for Parkinson’s disease. Biointerface Res. Appl. Chem. 2020 10 6 7135 7151 10.33263/BRIAC106.71357151
    [Google Scholar]
  86. Rahman M.M. Islam M.R. Akash S. Harun-Or-Rashid M. Ray T.K. Rahaman M.S. Islam M. Anika F. Hosain M.K. Aovi F.I. Hemeg H.A. Rauf A. Wilairatana P. Recent advancements of nanoparticles application in cancer and neurodegenerative disorders: At a glance. Biomed. Pharmacother. 2022 153 113305 10.1016/j.biopha.2022.113305 35717779
    [Google Scholar]
  87. Virameteekul S. Lees A.J. Bhidayasiri R. Small particles, big potential: Polymeric nanoparticles for drug delivery in Parkinson’s disease. Mov. Disord. 2024 39 11 1922 1937 10.1002/mds.29939 39077831
    [Google Scholar]
  88. Xu X. Liu C. Wang Y. Koivisto O. Zhou J. Shu Y. Zhang H. Nanotechnology-based delivery of CRISPR/Cas9 for cancer treatment. Adv. Drug Deliv. Rev. 2021 176 113891 10.1016/j.addr.2021.113891 34324887
    [Google Scholar]
  89. Ragelle H. Danhier F. Préat V. Langer R. Anderson D.G. Nanoparticle-based drug delivery systems: A commercial and regulatory outlook as the field matures. Expert Opin. Drug Deliv. 2017 14 7 851 864 10.1080/17425247.2016.1244187 27730820
    [Google Scholar]
  90. Duwa R. Jeong J.H. Yook S. Development of immunotherapy and nanoparticles-based strategies for the treatment of Parkinson’s disease. J. Pharm. Investig. 2021 51 4 465 481 10.1007/s40005‑021‑00521‑3
    [Google Scholar]
  91. Kim D. Yoo J.M. Hwang H. Lee J. Lee S.H. Yun S.P. Park M.J. Lee M. Choi S. Kwon S.H. Lee S. Kwon S.H. Kim S. Park Y.J. Kinoshita M. Lee Y.H. Shin S. Paik S.R. Lee S.J. Lee S. Hong B.H. Ko H.S. Graphene quantum dots prevent α-synucleinopathy in Parkinson’s disease. Nat. Nanotechnol. 2018 13 9 812 818 10.1038/s41565‑018‑0179‑y 29988049
    [Google Scholar]
  92. Hu M. Guo M. Fang H. Li H. Zhu K. Chen W. Wang Y. Wang S. Wei W. Co-delivery of NGF pDNA and shRNA targeting α-synuclein by gold nanoparticles for gene therapy of Parkinson’s disease. Biomater. Sci. 2018 6 5 1125 1136
    [Google Scholar]
  93. Gambaryan P.Y. Kondrasheva I.G. Severin E.S. Guseva A.A. Kamensky A.A. Increasing the efficiency of Parkinson’s disease treatment using a poly(lactic-co-glycolic acid) (PLGA)-based L-DOPA delivery system. Exp. Neurobiol. 2014 23 3 246 252 10.5607/en.2014.23.3.246 25258572
    [Google Scholar]
  94. Pahuja R. Seth K. Shukla A. Shukla R.K. Bhatnagar P. Chauhan L.K.S. Saxena P.N. Arun J. Chaudhari B.P. Patel D.K. Singh S.P. Shukla R. Khanna V.K. Kumar P. Chaturvedi R.K. Gupta K.C. Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats. ACS Nano 2015 9 5 4850 4871 10.1021/nn506408v 25825926
    [Google Scholar]
  95. Loureiro J.A. Gomes B. Fricker G. Coelho M.A.N. Rocha S. Pereira M.D.C. Santos de Almeida E. Dual-targeted liposomes for drug delivery to the brain: Targeting α-synuclein and transferrin receptors. J. Control. Release 2015 206 1 13
    [Google Scholar]
  96. Mandler M. Valera E. Rockenstein E. Weninger H. Patrick C. Adame A. Schmidhuber S. Santic R. Schneeberger A. Schmidt W. Masliah E. Active immunization against α-synuclein ameliorates the degenerative pathology and memory deficits in a mouse model of Parkinson’s disease. Acta Neuropathol. 2014 127 5 619 638
    [Google Scholar]
  97. Naahidi S. Jafari M. Edalat F. Raymond K. Khademhosseini A. Chen P. Biocompatibility of engineered nanoparticles for drug delivery. J. Control. Release 2013 166 2 182 194 10.1016/j.jconrel.2012.12.013 23262199
    [Google Scholar]
  98. Chatterji T. Khanna N. Kumari M. Singh A.K. Thakur N. Kumar U. Development of personalized medicine: Challenges and therapeutic applications. In: Nanotherapeutics for Inflammatory Arthritis. CRC Press 2024 121 142
    [Google Scholar]
  99. Fang Y. Wang J. Zhao M. Zheng Q. Ren C. Wang Y. Zhang J. Progress and challenges in targeted protein degradation for neurodegenerative disease therapy. J. Med. Chem. 2022 65 17 11454 11477 10.1021/acs.jmedchem.2c00844 36006861
    [Google Scholar]
  100. Mansour H.M. El-Khatib A.S. Exploring Parkinson-associated kinases for CRISPR/Cas9-based gene editing: Beyond alpha-synuclein. Ageing Res. Rev. 2023 92 102114 10.1016/j.arr.2023.102114 37924981
    [Google Scholar]
  101. Mazumdar H. Khondakar K.R. Das S. Halder A. Kaushik A. Artificial intelligence for personalized nanomedicine; from material selection to patient outcomes. Expert Opin. Drug Deliv. 2025 22 1 85 108 10.1080/17425247.2024.2440618 39645588
    [Google Scholar]
  102. Saraiva M.F.F. Synthesis and evaluation of biodegradable diamine terminated PEG-GATGE dendrimers as vectors for the delivery of siRNA. INEB - National Institute of Biomedical Engineering 2022
    [Google Scholar]
  103. Calabresi P. Mechelli A. Natale G. Volpicelli-Daley L. Di Lazzaro G. Ghiglieri V. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: From overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 2023 14 3 176 10.1038/s41419‑023‑05672‑9 36859484
    [Google Scholar]
  104. Pardeshi C. Souto E.B. eds Direct Nose-to-Brain Drug Delivery: Mechanism, Technological Advances, Applications, and Regulatory Updates; Elsevier 2021 9780128225226Jun
    [Google Scholar]
  105. Yadav K. Vijayalakshmi R. Kumar Sahu K. Sure P. Chahal K. Yadav R. Sucheta; Dubey, A.; Jha, M.; Pradhan, M. Exosome-Based Macromolecular neurotherapeutic drug delivery approaches in overcoming the Blood-Brain barrier for treating brain disorders. Eur. J. Pharm. Biopharm. 2024 199 114298 10.1016/j.ejpb.2024.114298 38642716
    [Google Scholar]
/content/journals/dmb/10.2174/0118723128397400250910222116
Loading
Novel Therapeutic Strategies in Targeting Alpha Synuclein Dysfunction Pathways for Parkinson’s Disease Treatment
Bentham Science Publishers ; https://doi.org/10.2174/0118723128397400250910222116
/content/journals/dmb/10.2174/0118723128397400250910222116
/content/journals/dmb/10.2174/0118723128397400250910222116
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: nano-technological drug delivery ; small molecules ; immunotherapy ; Alpha-Synuclein dysfunction ; gene therapy ; Parkinson's disease
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test