Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2

Academic Neurology Unit, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
Neurology (Impact Factor: 8.29). 11/2010; 75(22):2017-20. DOI: 10.1212/WNL.0b013e3181ff9685
Source: PubMed


The LRRK2(G2019S) mutation is the most common identifiable cause for Parkinson disease (PD), but the underlying mechanisms leading to neuronal cell death remain largely unclear. Impaired mitochondrial function and morphology have been described in different in vivo and in vitro model systems of early-onset PD (EOPD) as well as in EOPD patient tissue. The aim of our study was to assess mitochondrial function and morphology in LRRK2(G2019S) mutant patient tissue to determine whether impaired mitochondrial function and morphology are shared features in early-onset and late-onset PD.
Skin biopsies were taken from 5 patients with PD with the LRRK2(G2019S) mutation. Assessment of mitochondrial membrane potential and intracellular ATP levels as well as substrate-linked mitochondrial ATP production assays were all carried out on 3 independent cell preparations per patient. Results were compared to 5 age-matched controls. Mitochondrial elongation and interconnectivity was assessed using previously published methods.
Both mitochondrial membrane potential and total intracellular ATP levels were decreased in the G2019S mutation carriers. Subsequently undertaken mitochondrial ATP production assays suggested that the observed reduction is at least partially due to impaired mitochondrial function. Mitochondrial elongation and interconnectivity were increased in the LRRK2(G2019S) patient cohort.
Our results provide evidence for impaired mitochondrial function and morphology in LRRK2(G2019S) mutant patient tissue. Further studies are required to determine whether the impaired mitochondrial function is due to increased LRRK2 kinase activity or other mechanisms such as LRRK2 haploinsufficiency.

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    • "No structural mitochondria abnormality is observed in mouse neurons that overexpress either WT or mutant LRRK2 (Lin et al., 2009). In skin biopsies from human LRRK2 G2019S carriers, however, mitochondrial function and morphology are perturbed characterized by reduced mitochondrial membrane potential, reduced intracellular ATP levels, mitochondrial elongation, and increased mitochondrial interconnectivity (Mortiboys et al., 2010). In contrast to this, in cortical neurons LRRK2 G2019S overexpression increases DLP-1 activity and promotes mitochondrial fission (Niu et al., 2012; Wang et al., 2012). "
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    ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity. Kinase and GTPase domains are involved in different cellular signalling pathways. Despite several experimental studies associating LRRK2 protein with various intracellular membranes and vesicular structures such as endosomal/lysosomal compartments, the mitochondrial outer membrane, lipid rafts, microtubule-associated vesicles, the golgi complex, and the endoplasmic reticulum its broader physiologic function(s) remain unidentified. Additionally, the cellular distribution of LRRK2 may indicate its role in several different pathways, such as the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction. This review discusses potential mechanisms through which LRRK2 may mediate neurodegeneration and cause PD.
    Experimental Neurology 06/2014; 261. DOI:10.1016/j.expneurol.2014.05.025 · 4.70 Impact Factor
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    • "However, the physiological role of LRRK2 and the way that its activity is altered by pathogenic mutations are currently unknown. Several studies have implicated LRRK2 in the regulation of autophagy, whereas others have provided evidence that, similar to the other PD-related proteins , also LRRK2 mutations are responsible for alterations in mitochondrial morphology and function, i.e., in ATP production (Mortiboys et al. 2010). Data regarding a possible link between LRRK2 and Ca 2+ signaling are scarce. "
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    ABSTRACT: Calcium (Ca(2+)) is an almost universal second messenger that regulates important activities of all eukaryotic cells. It is of critical importance to neurons, which have developed extensive and intricate pathways to couple the Ca(2+) signal to their biochemical machinery. In particular, Ca(2+) participates in the transmission of the depolarizing signal and contributes to synaptic activity. During aging and in neurodegenerative disease processes, the ability of neurons to maintain an adequate energy level can be compromised, thus impacting on Ca(2+) homeostasis. In Parkinson's disease (PD), many signs of neurodegeneration result from compromised mitochondrial function attributable to specific effects of toxins on the mitochondrial respiratory chain and/or to genetic mutations. Despite these effects being present in almost all cell types, a distinguishing feature of PD is the extreme selectivity of cell loss, which is restricted to the dopaminergic neurons in the ventral portion of the substantia nigra pars compacta. Many hypotheses have been proposed to explain such selectivity, but only recently it has been convincingly shown that the innate autonomous activity of these neurons, which is sustained by their specific Cav1.3 L-type channel pore-forming subunit, is responsible for the generation of basal metabolic stress that, under physiological conditions, is compensated by mitochondrial buffering. However, when mitochondria function becomes even partially compromised (because of aging, exposure to environmental factors or genetic mutations), the metabolic stress overwhelms the protective mechanisms, and the process of neurodegeneration is engaged. The characteristics of Ca(2+) handling in neurons of the substantia nigra pars compacta and the possible involvement of PD-related proteins in the control of Ca(2+) homeostasis will be discussed in this review.
    Cell and Tissue Research 05/2014; 357(2). DOI:10.1007/s00441-014-1866-0 · 3.57 Impact Factor
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    • "Mutations in Pink1 and Parkin have been shown to cause a loss of mitochondrial ultrastructure as observed as changes in the electron density of the mitochondria and fragmentation of the mitochondrial network (Clark et al. 2006; Greene et al. 2003). A loss of DJ‐1 causes a loss of mitochondrial membrane potential and M a n u s c r i p t increased mitochondrial fragmentation (Thomas et al. 2010; Wang et al. 2012) and mitochondrial changes have also been reported when LRRK2 (Leucine rich repeat kinase 2) is mutated (Goo et al. 2013; Mortiboys et al. 2010). A recent paper has also shown that mitofusin2 (mfn2), a protein important for mitochondrial fusion, is essential for the survival of striatal projections from the SN. "
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    ABSTRACT: As the second most common age related neurodegenerative disease after Alzheimer's disease, the health, social and economic impact resulting from Parkinson's disease will continue to increase alongside the longevity of the population. Ageing remains the biggest risk factor for developing idiopathic Parkinson's disease. Although research into the mechanisms leading to cell death in Parkinson's disease has shed light on many aspects of the pathogenesis of this disorder, we still cannot answer the fundamental question, what specific age related factors predispose some individuals to develop this common neurodegenerative disease. In this review we focus specifically on the neuronal population associated with the motor symptoms of Parkinson's disease, the dopaminergic neurons of the substantia nigra, and try to understand how ageing puts these neurons at risk to the extent that a slight change in protein metabolism or mitochondrial function can push the cells over the edge leading to catastrophic cell death and many of the symptoms seen in Parkinson's disease. We review the evidence that ageing is important for the development of Parkinson's disease and how age related decline leads to the loss of neurons within this disease, before describing exactly how advancing age may lead to substantia nigra neuronal loss and Parkinson's disease in some individuals.
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