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. 2017 Aug 24;10:265.
doi: 10.3389/fnmol.2017.00265. eCollection 2017.

Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome

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Free PMC article

Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome

Byron Chen et al. Front Mol Neurosci. .
Free PMC article

Abstract

Inability of mitochondria to generate energy leads to severe and often fatal myoencephalopathies. Among these, Leigh syndrome (LS) is one of the most common childhood mitochondrial diseases; it is characterized by hypotonia, failure to thrive, respiratory insufficiency and progressive mental and motor dysfunction, leading to early death. Basal ganglia nuclei, including the striatum, are affected in LS patients. However, neither the identity of the affected cell types in the striatum nor their contribution to the disease has been established. Here, we used a mouse model of LS lacking Ndufs4, a mitochondrial complex I subunit, to confirm that loss of complex I, but not complex II, alters respiration in the striatum. To assess the role of striatal dysfunction in the pathology, we selectively inactivated Ndufs4 in the striatal medium spiny neurons (MSNs), which account for over 95% of striatal neurons. Our results show that lack of Ndufs4 in MSNs causes a non-fatal progressive motor impairment without affecting the cognitive function of mice. Furthermore, no inflammatory responses or neuronal loss were observed up to 6 months of age. Hence, complex I deficiency in MSNs contributes to the motor deficits observed in LS, but not to the neural degeneration, suggesting that other neuronal populations drive the plethora of clinical signs in LS.

Keywords: animal; behavior; medium spiny neuron; mitochondrial disease; mouse genetics; striatum.

Figures

Figure 1
Figure 1
Complex I-mediated respiratory alterations in Ndufs4 knockout (KO) mice. (A) Complex I-dependent respiration (using pyruvate/malate as substrates) and (B) complex II-mediated respiration (using succinate as substrate) in striata from Ndufs4 KO mice (n = 5) compared to wild-type (WT) mice (n = 5). Basal: 500 mM malate and 500 mM pyruvate (CI) or 500 mM succinate and 2 mM of the CI inhibitor rotenone (CII). ADP (40 mM) initiated state III, oligomycin (25 μg/mL) induced state IVo, FCCP (50 μM) induced an uncoupled state and antimycin A (40 μg/μL) induced complete electron transport chain inhibition. **p < 0.01, ***p < 0.001 vs. WT. Data are shown as mean ± SEM.
Figure 2
Figure 2
Generation of a mouse line lacking Ndufs4 in the striatal medium spiny neurons (MSNs). (A) Breeding strategy to generate animals with conditional Ndufs4 deletion in striatal MSNs (MSN KO) and their genetic controls (MSN CTL). (B) Body weight curves for MSN KO mice (n = 5 males, n = 6 females) and MSN CTL (n = 14 males, n = 11 females). (C) Representative western blot analyses of total Ndufs4 and β-Actin (loading control) in the striatum and brainstem of MSN KO and CTL mice (n = 3). Data are shown as mean ± SEM.
Figure 3
Figure 3
Reduced activity in MSN KO mice. Spontaneous activity was recorded for 48 h. Activity pattern (A) and quantification of nocturnal activity (B) of 2-month-old MSN KO (n = 6) and MSN CTL mice (n = 6). (C) Activity pattern and (D) quantification of nocturnal activity of 6-month-old MSN CTL (n = 7) and MSN KO mice (n = 8); **p < 0.01. Data are shown as mean ± SEM.
Figure 4
Figure 4
Motor alterations but intact associative learning in MSN KO mice. (A) Rotarod performance of MSN KO mice (n = 13) and MSN CTL mice (n = 26). (B) Water U-maze performance of 6-month-old MSN KO mice (n = 7) and MSN CTL mice (n = 8). Animals were trained for 3 days on a turn-based escape procedure and subsequently forced to change to a cue-based escape strategy. ***p < 0.001 vs. Ndufs4cCTGpr88. Data are shown as mean ± SEM.
Figure 5
Figure 5
Lack of reactive gliosis in the striatum or neuronal loss after Ndufs4 ablation in MSNs. (A) Representative GFAP (red) and Iba1 (green) immunofluorescence in striatum (Str) of MSN KO and MSN CTL mice. cc: corpus callosum. lv: lateral ventricle. (B,C) Representative western blot analyses of GFAP, Iba1, NSE and β-actin and GAPDH (loading controls) and quantification (C) in the striatum and brainstem of MSN KO and MSN CTL mice (n = 3–9). Data are shown as mean ± SEM.

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