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Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson's disease.
J Transl Med 2018; 16(1):160JT

Abstract

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.

Authors+Show Affiliations

Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Laboratory of Parkinson disease and other Neurodegenerative Movement Disorders: Clinical and Experimental Research, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain. CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Laboratory of Parkinson disease and other Neurodegenerative Movement Disorders: Clinical and Experimental Research, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain. CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.Laboratory of Parkinson disease and other Neurodegenerative Movement Disorders: Clinical and Experimental Research, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain. CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.Laboratory of Parkinson disease and other Neurodegenerative Movement Disorders: Clinical and Experimental Research, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain. CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. cmoren1@clinic.ub.es. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. cmoren1@clinic.ub.es.Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. garrabou@clinic.ub.es. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. garrabou@clinic.ub.es.

Pub Type(s)

Journal Article
Observational Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29884186

Citation

Juárez-Flores, Diana Luz, et al. "Exhaustion of Mitochondrial and Autophagic Reserve May Contribute to the Development of LRRK2 G2019S -Parkinson's Disease." Journal of Translational Medicine, vol. 16, no. 1, 2018, p. 160.
Juárez-Flores DL, González-Casacuberta I, Ezquerra M, et al. Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson's disease. J Transl Med. 2018;16(1):160.
Juárez-Flores, D. L., González-Casacuberta, I., Ezquerra, M., Bañó, M., Carmona-Pontaque, F., Catalán-García, M., ... Garrabou, G. (2018). Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson's disease. Journal of Translational Medicine, 16(1), p. 160. doi:10.1186/s12967-018-1526-3.
Juárez-Flores DL, et al. Exhaustion of Mitochondrial and Autophagic Reserve May Contribute to the Development of LRRK2 G2019S -Parkinson's Disease. J Transl Med. 2018 06 8;16(1):160. PubMed PMID: 29884186.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson's disease. AU - Juárez-Flores,Diana Luz, AU - González-Casacuberta,Ingrid, AU - Ezquerra,Mario, AU - Bañó,María, AU - Carmona-Pontaque,Francesc, AU - Catalán-García,Marc, AU - Guitart-Mampel,Mariona, AU - Rivero,Juan José, AU - Tobias,Ester, AU - Milisenda,Jose Cesar, AU - Tolosa,Eduard, AU - Marti,Maria Jose, AU - Fernández-Santiago,Ruben, AU - Cardellach,Francesc, AU - Morén,Constanza, AU - Garrabou,Glòria, Y1 - 2018/06/08/ PY - 2018/02/08/received PY - 2018/05/26/accepted PY - 2018/6/10/entrez PY - 2018/6/10/pubmed PY - 2019/6/15/medline KW - Autophagy KW - Fibroblasts KW - G2019S KW - Galactose KW - Glucose KW - LRRK2 KW - Mitochondrial dynamics KW - Mitochondrial dysfunction KW - Non-manifesting carriers KW - Parkinson’s disease SP - 160 EP - 160 JF - Journal of translational medicine JO - J Transl Med VL - 16 IS - 1 N2 - 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. SN - 1479-5876 UR - https://www.unboundmedicine.com/medline/citation/29884186/Exhaustion_of_mitochondrial_and_autophagic_reserve_may_contribute_to_the_development_of_LRRK2_G2019S__Parkinson's_disease_ L2 - https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1526-3 DB - PRIME DP - Unbound Medicine ER -