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protein aggregates in Lewy\u2019s Bodies the histopathological hallmark of the disease. Although different gene variants are linked to Parkinson disease, mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are one of the most frequent causes of Parkinson\u2019s disease related to genetic mutations. LRRK2 toxicity has been mainly explained by an increase in kinase activity, but alternative mechanisms have emerged as underlying causes for Parkinson\u2019s disease, such as the imbalance in LRRK2 homeostasis and the involvement of LRRK2 in aggregation and spreading of \u03b1-synuclein toxicity. In this review, we recapitulate the main LRRK2 pathological mutations that contribute to Parkinson\u2019s disease and the different cellular and therapeutic strategies devised to correct LRRK2 homeostasis. In this review, we describe the main cellular control mechanisms that regulate LRRK2 folding and aggregation, such as the chaperone network and the protein-clearing pathways such as the ubiquitin\u2013proteasome system and the autophagic-lysosomal pathway. We will also address the more relevant strategies to modulate neurodegeneration in Parkinson\u2019s disease through the regulation of LRRK2, using small molecules or LRRK2 silencing.<\/jats:p>","DOI":"10.3390\/ijms23126808","type":"journal-article","created":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T09:51:11Z","timestamp":1655545871000},"page":"6808","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["LRRK2 and Proteostasis in Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0178-173X","authenticated-orcid":false,"given":"Mar\u00eda Dolores","family":"P\u00e9rez-Carri\u00f3n","sequence":"first","affiliation":[{"name":"Unidad Asociada Neurodeath, Universidad de Castilla-La Mancha, 02006 Albacete, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas, Consorcio CIBER, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1854-3372","authenticated-orcid":false,"given":"Inmaculada","family":"Posadas","sequence":"additional","affiliation":[{"name":"Unidad Asociada Neurodeath, Universidad de Castilla-La Mancha, 02006 Albacete, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas, Consorcio CIBER, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Solera","sequence":"additional","affiliation":[{"name":"Servicio de Medicina Interna, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain"},{"name":"Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, 02006 Albacete, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8928-3681","authenticated-orcid":false,"given":"Valent\u00edn","family":"Ce\u00f1a","sequence":"additional","affiliation":[{"name":"Unidad Asociada Neurodeath, Universidad de Castilla-La Mancha, 02006 Albacete, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas, Consorcio CIBER, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1002\/mds.27115","article-title":"Past, present, and future of Parkinson\u2019s disease: A special essay on the 200th Anniversary of the Shaking Palsy","volume":"32","author":"Obeso","year":"2017","journal-title":"Mov. 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