Analysis of LRRK2 Towards understanding the pathogenic mechanisms underlying parkinson's disease: Deregulated autophagy and endocytosis
Metadatos
Afficher la notice complèteAuteur
Gómez Suaga, Patricia MaríaEditorial
Universidad de Granada
Director
Navarro Hilfiker, Sabine NicoleDepartamento
Universidad de Granada. Programa Oficial de Doctorado en: Biomedicina Regenerativa; Consejo Superior de Investigaciones Científicas (CSIC). Instituto de Parasitología y Biomedicina López-NeyraMateria
Enfermedad de Parkinson Endocitosis LRRK2 Fagocitosis Genética Autofagia Enfermedades lisosomales
Materia UDC
615.8 310802
Date
2017Fecha lectura
2014-04-11Referencia bibliográfica
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]
Patrocinador
Tesis Univ. Granada. Programa Oficial de Doctorado en: Biomedicina RegenerativaRésumé
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.