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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/45093

Title: Analysis of LRRK2 Towards understanding the pathogenic mechanisms underlying parkinson's disease: Deregulated autophagy and endocytosis
Authors: Gómez Suaga, Patricia María
Direction: Navarro Hilfiker, Sabine Nicole
Collaborator: Universidad de Granada. Programa Oficial de Doctorado en: Biomedicina Regenerativa
Consejo Superior de Investigaciones Científicas (CSIC). Instituto de Parasitología y Biomedicina "López-Neyra"
Issue Date: 2017
Submitted Date: 11-Apr-2014
Abstract: Although the majority of PD cases are idiopathic, the identification of diseasecausing mutations helps in our understanding of the molecular mechanisms involved in neuronal demise. Mutations in LRRK2 (leucine-rich repeat kinase 2) are found associated with both sporadic and familial Parkinson´s disease (PD). LRRK2 is a multidomain protein characterised by kinase and GTPase activities, with pathogenic mutations localized to both catalytic domains. There is a significant body of evidence correlating altered catalytic activity with cytotoxicity. However, early cellular LRRK2- mediated events which eventually lead to cellular demise remain poorly understood. LRRK2 has been implicated in autophagic and endosomal trafficking pathways in vitro and in vivo, even though the mechanism(s) remain unclear. This thesis describes work towards addressing how pathogenic LRRK2 may cause cellular dysfunction linked to PD pathogenesis, with emphasis on autophagy and endosomal trafficking deficits. First, mutant LRRK2 was found to cause a block in autophagic flux through a pathway involving NAADP (nicotinic acid adenine dinucleotide phosphate)-sensitive channels in acidic late endosomal/lysosomal structures. Pathogenic LRRK2 was found to cause a partial increase in lysosomal pH, and decreased cell survival in the presence of protein aggregation-induced stress. Since autophagy and endocytosis share late endosomes/lysosomes as common end-points, the effect of mutant LRRK2 on endocytosis was evaluated. Pathogenic LRRK2 was found to cause deficits in both early and late events of receptor-mediated endocytosis, including a delay in receptor trafficking out of late endosomes, which become aberrantly elongated. Rab7 is a small GTPase involved in various endosomal trafficking processes, including late endosomal-lysosomal trafficking and retromer-mediated trafficking between late endosomes and the trans-Golgi network. The effects on receptor trafficking could be rescued when overexpressing constitutively active Rab7 or Rab7L1, as well as the Rab7-interacting proteins dynamin2/CIN85, which localize to late endosomes and regulate degradative receptor trafficking. Pathogenic LRRK2 expression was associated with a decrease in Rab7 activity. Alltogether, the present results highlight an important role for pathogenic LRRK2 in deregulating several endolysosomal membrane trafficking events, which may underlie early cellular pathogenesis in PD.
Sponsorship: Tesis Univ. Granada. Programa Oficial de Doctorado en: Biomedicina Regenerativa
Publisher: Universidad de Granada
Keywords: Enfermedad de Parkinson
Endocitosis
LRRK2
Fagocitosis
Genética
Autofagia
Enfermedades lisosomales
UDC: 615.8
310802
URI: http://hdl.handle.net/10481/45093
ISBN: 9788491631262
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: Gómez Suaga, P.M. Analysis of LRRK2 Towards understanding the pathogenic mechanisms underlying parkinson's disease: Deregulated autophagy and endocytosis. Granada: Universidad de Granada, 2017. [http://hdl.handle.net/10481/45093]
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