Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson's disease

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RECERCAT Home > Universitat de Barcelona > IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer > Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) > View document

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dc.contributor.author	Juárez Flores, Diana Luz
dc.contributor.author	González Casacuberta, Ingrid
dc.contributor.author	Ezquerra, Mario
dc.contributor.author	Bañó, Maria
dc.contributor.author	Carmona Pontaque, Francesc
dc.contributor.author	Catalán García, Marc
dc.contributor.author	Guitart Mampel, Mariona
dc.contributor.author	Rivero, Juan José
dc.contributor.author	Tobías Baraja, Ester
dc.contributor.author	Milisenda, José
dc.contributor.author	Tolosa, Eduardo
dc.contributor.author	Martí Domènech, Ma. Josep
dc.contributor.author	Fernández Santiago, Rubén
dc.contributor.author	Cardellach, Francesc
dc.contributor.author	Morén Núñez, Constanza
dc.contributor.author	Garrabou Tornos, Glòria
dc.date	2019-05-09T11:43:03Z
dc.date	2019-05-09T11:43:03Z
dc.date	2018-06-08
dc.date	2019-05-09T11:43:03Z
dc.identifier	1479-5876
dc.identifier	http://hdl.handle.net/2445/132882
dc.identifier	681148
dc.identifier.uri	http://hdl.handle.net/2445/132882
dc.description	BACKGROUND: Mutations in leucine rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). Mitochondrial and autophagic dysfunction has been described as etiologic factors in different experimental models of PD. We aimed to study the role of mitochondria and autophagy in LRRK2 G2019S -mutation, and its relationship with the presence of PD-symptoms. METHODS: Fibroblasts from six non-manifesting LRRK2 G2019S -carriers (NM-LRRK2 G2019S ) and seven patients with LRRK2 G2019S -associated PD (PD-LRRK2 G2019S ) were compared to eight healthy controls (C). An exhaustive assessment of mitochondrial performance and autophagy was performed after 24-h exposure to standard (glucose) or mitochondrial-challenging environment (galactose), where mitochondrial and autophagy impairment may be heightened. RESULTS: A similar mitochondrial phenotype of NM-LRRK2 G2019S and controls, except for an early mitochondrial depolarization (54.14% increased, p = 0.04), was shown in glucose. In response to galactose, mitochondrial dynamics of NM-LRRK2 G2019S improved (- 17.54% circularity, p = 0.002 and + 42.53% form factor, p = 0.051), probably to maintain ATP levels over controls. A compromised bioenergetic function was suggested in PD-LRRK2 G2019S when compared to controls in glucose media. An inefficient response to galactose and worsened mitochondrial dynamics (- 37.7% mitochondrial elongation, p = 0.053) was shown, leading to increased oxidative stress. Autophagy initiation (SQTSM/P62) was upregulated in NM-LRRK2 G2019S when compared to controls (glucose + 118.4%, p = 0.014; galactose + 114.44%, p = 0.009,) and autophagosome formation increased in glucose media. Despite of elevated SQSTM1/P62 levels of PD-NM G2019S when compared to controls (glucose + 226.14%, p = 0.04; galactose + 78.5%, p = 0.02), autophagosome formation was deficient in PD-LRRK2 G2019S when compared to NM-LRRK2 G2019S (- 71.26%, p = 0.022). CONCLUSIONS: Enhanced mitochondrial performance of NM-LRRK2 G2019S in mitochondrial-challenging conditions and upregulation of autophagy suggests that an exhaustion of mitochondrial bioenergetic and autophagic reserve, may contribute to the development of PD in LRRK2 G2019S mutation carriers.
dc.format	14 p.
dc.format	application/pdf
dc.language	eng
dc.publisher	BioMed Central
dc.relation	Reproducció del document publicat a: https://doi.org/10.1186/s12967-018-1526-3
dc.relation	Journal of Translational Medicine, 2018, vol. 16, num. 1, p. 160-173
dc.relation	https://doi.org/10.1186/s12967-018-1526-3
dc.rights	cc-by (c) Juárez Flores, Diana Luz et al., 2018
dc.rights	http://creativecommons.org/licenses/by/3.0/es
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Malaltia de Parkinson
dc.subject	Autofàgia
dc.subject	Fibroblasts
dc.subject	Mitocondris
dc.subject	Parkinson's disease
dc.subject	Autophagy
dc.subject	Fibroblasts
dc.subject	Mitochondria
dc.title	Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson's disease
dc.type	info:eu-repo/semantics/article
dc.type	info:eu-repo/semantics/publishedVersion

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