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Although the underlying molecular etiology of these pathological processes remains unclear, progressive aggregation of alpha-synuclein (\u03b1-syn) and mitochondrial dysfunction are two expected mechanisms implicated in neuronal degeneration. Accumulating evidence indicates that transition metal dichalcogenide (TMD) nanoflowers (NFs), a novel class of nanomaterials, can restore mitochondrial health by the activation of mitochondrial biogenesis. However, therapeutic potential of TMD NFs in PD remains unclear. The current study investigates the neuroprotective properties of molybdenum disulfide (MoS\n                  <jats:sub>2<\/jats:sub>\n                  ) and molybdenum diselenide (MoSe\n                  <jats:sub>2<\/jats:sub>\n                  ) nanoflowers (NFs) in neurons and astrocytes exposed to \u03b1-syn aggregates. It was found that MoS\n                  <jats:sub>2<\/jats:sub>\n                  and MoSe\n                  <jats:sub>2<\/jats:sub>\n                  suppressed \u03b1-syn-induced unfolded protein response (UPR) in the endoplasmic reticulum, and upregulated autophagy and exocytosis of \u03b1-syn fibrils. TMD NFs also reversed \u03b1-syn-induced damage of cell mitochondria, simultaneously stimulating mitochondrial biogenesis. As a result, a drastic decrease in ROS levels in both neurons and astrocytes was observed. These results show that MoS\n                  <jats:sub>2<\/jats:sub>\n                  or MoSe\n                  <jats:sub>2<\/jats:sub>\n                  NFs could fully rescue neurons and astrocytes from the cytotoxic effects of \u03b1-syn fibrils. Neuroprotective properties of these novel nanomaterials were further explored in\n                  <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                  that overexpress \u03b1-syn. Nematodes that received NFs experienced a drastic reduction in the amount of aggregated \u03b1-syn which resulted in a significant increase in\n                  <jats:italic>C. elegans<\/jats:italic>\n                  lifespan. These findings indicated that MoS\n                  <jats:sub>2<\/jats:sub>\n                  or MoSe\n                  <jats:sub>2<\/jats:sub>\n                  NFs could be used as novel therapeutic to decelerate the progression of PD.\n                <\/jats:p>","DOI":"10.1101\/2025.09.29.679305","type":"posted-content","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T20:45:11Z","timestamp":1759351511000},"source":"Crossref","is-referenced-by-count":1,"title":["Neuroprotective Parkinson\u2019s Disease Therapeutic: Transition Metal Dichalcogenide Nanoflower Treatments Alleviate Pathological Cell Stress"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0992-1572","authenticated-orcid":false,"given":"Charles L.","family":"Mitchell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikhail","family":"Matveyenka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harris C.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Aldape","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Payton","family":"Moore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kha-Tran","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryce","family":"Pearson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Skrehot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry","family":"Kurouski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025100320051342000_2025.09.29.679305v1.1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2024-080952"},{"key":"2025100320051342000_2025.09.29.679305v1.2","doi-asserted-by":"crossref","first-page":"e10367","DOI":"10.1002\/btm2.10367","article-title":"Alzheimer\u2019s and Parkinson\u2019s disease therapies in the clinic","volume":"8","year":"2023","journal-title":"Bioeng Transl Med"},{"key":"2025100320051342000_2025.09.29.679305v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-100720-034518"},{"key":"2025100320051342000_2025.09.29.679305v1.4","doi-asserted-by":"crossref","unstructured":"C. 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