Mitochondria mass is low in mouse substantia nigra dopamine neurons: implications for Parkinson's disease.
ABSTRACT In Parkinson's disease (PD) there is a selective loss of certain midbrain dopaminergic (DA) neurons. The most vulnerable neurons reside in the substantia nigra zona compacta (SNC), whereas the DA neurons in the ventral tegmental area (VTA) and interfascicular (IF) nucleus are less vulnerable to degeneration. Many sporadic PD patients have a defect in mitochondria respiration, and some of the genes that cause PD are mitochondrial-related (e.g., PINK1, Parkin, DJ1). The present study sought to determine whether mitochondria mass is different in SNC neurons compared to other midbrain DA neurons and to non-DA neurons in the mouse. At the electron microscopic level, mitochondria in the SN DA neurons occupy 40% less of the soma and dendritic area than in the SN non-DA neurons. The area occupied by mitochondria in the SN DA neurons is also lower than in the VTA neurons, although not different from the IF neurons. The red nucleus somata have the largest percentage of the somata occupied by mitochondria (12%). Mitochondria size is related to somata size; the largest mitochondria are found in the red nucleus neurons and the smallest mitochondria are found in the IF neurons. At the light microscopic level, SNC, VTA and IF DA neurons have <50% of the cytoplasm immunostained with the mitochondrial antibody 1D6, whereas non-DA neurons in the same midbrain regions contain mitochondria areas up to >65% of the cytoplasm area. These data indicate that mitochondria size and mass are not the same for all neurons, and the SNC DA neurons have relatively low mitochondria mass. The low mitochondria mass in SNC DA neurons may contribute to the selective vulnerability of these neurons in certain rodent models of PD.
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ABSTRACT: The mitochondrial transporter of aspartate-glutamate Aralar/AGC1 is a regulatory component of the malate-aspartate shuttle. Aralar-deficiency in mouse and human causes a shutdown of brain shuttle activity and global cerebral hypomyelination. A lack of neurofilament-labelled processes is detected in the cerebral cortex, but whether different types of neurons are differentially affected by Aralar-deficiency is still unknown. We have now found that Aralar-knockout (Aralar-KO) postnatal mice show hyperactivity, anxiety-like behaviour and hyperreactivity with a decrease of dopamine (DA) in terminal-rich regions. The striatum is the brain region most affected in terms of size, amino acid and monoamine content. We find a decline in vesicular monoamine transporter-2 (VMAT2) levels associated with increased DA metabolism through MAO activity (DOPAC/DA ratio) in Aralar-KO striatum. However, no decrease in DA or in the number of nigral tyrosine hydroxylase-positive cells was detected in Aralar-KO brainstem. Adult Aralar-hemizygous mice presented also increased DOPAC/DA ratio in striatum and enhanced sensitivity to amphetamine. Our results suggest that Aralar-deficiency causes a fall in GSH/GSSG ratio and VMAT2 in striatum that might be related to a failure to produce mitochondrial NADH and to an increase of ROS in the cytosol. The results indicate that the nigrostriatal dopaminergic system is a target of Aralar-deficiency. ©2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12096.Journal of Neurochemistry 12/2012; DOI:10.1111/jnc.12096 · 4.24 Impact Factor
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ABSTRACT: Mitochondrial dysfunctions are very common features of age-related neurological diseases such as Parkinson ' s, Alzheimer ' s and Huntington ' s disease. Several studies have shown that bioenergetic impairments have a major role in the degeneration of the central nervous system (CNS) in these patients. Accordingly, one of the main symptoms in many mitochondrial diseases is severe encephalopathy. The het-erogeneity of the brain in terms of anatomic structures, cell composition, regional functions and biochemical properties makes the analysis on this organ very complex and diffi cult to interpret. Humans, in addition to animal models, exposed to toxins that affect mitochondrial function, in particular oxidative phosphorylation, exhibit degeneration of specifi c regions within the brain. Moreover, mutations in ubiquitously expressed genes that are involved in mitochondrial function also induce regional-specifi c cell death in the CNS. In this review, we will discuss some current hypotheses to explain the regional susceptibilities to mitochondrial dysfunctions in the CNS.Biological Chemistry 05/2012; 393(4):275-281. DOI:10.1515/hsz-2011-0236 · 2.69 Impact Factor
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ABSTRACT: Polyglutamine expansion mutation in huntingtin causes Huntington's disease (HD). How mutant huntingtin (mHtt) preferentially kills striatal neurons remains unknown. The link between mitochondrial dysfunction and HD pathogenesis stemmed from postmortem brain data and mitochondrial toxin models. Current evidence from genetic models, containing mHtt, supports mitochondrial dysfunction with yet uncertain nature and cause. Because mitochondria composition and function varies across tissues and cell-types, mitochondrial dysfunction in HD vulnerable striatal neurons may have distinctive features. This review focuses on mHtt and the striatum, integrating experimental evidence from patients, mice, primary cultures and striatal cell-lines. I address the nature (specific deficits) and cause (mechanisms linked to mHtt) of HD mitochondrial dysfunction, considering limitations of isolated vs. in situ mitochondria approaches, and the complications introduced by glia and glycolysis in brain and cell-culture studies. Current evidence relegates respiratory chain impairment to a late secondary event. Upstream events include defective mitochondrial calcium handling, ATP production and trafficking. Also, transcription abnormalities affecting mitochondria composition, reduced mitochondria trafficking to synapses, and direct interference with mitochondrial structures enriched in striatal neurons, are possible mechanisms by which mHtt amplifies striatal vulnerability. Insights from common neurodegenerative disorders with selective vulnerability and mitochondrial dysfunction (Alzheimer's and Parkinson's diseases) are also addressed.Journal of Neurochemistry 07/2010; 114(1):1-12. DOI:10.1111/j.1471-4159.2010.06741.x · 4.24 Impact Factor