To determine how mitochondrial fission affects mitochondrial behavior in axons and how this, in turn, affects axonal integrity and neuronal survival, we selectively deleted Drp1 in DA neurons. Drosophila with impaired mitochondrial fission also have fewer mitochondria at the neuromuscular junction ( Verstreken et al., 2005), although the mechanism underlying this depletion is not understood. However, the functional consequences of any changes in mitochondrial turnover are unclear, and immortalized mouse embryonic fibroblasts that lack Drp1 have normal respiration ( Ishihara et al., 2009 Wakabayashi et al., 2009). Mitochondrial fission can help sequester poorly functioning (depolarized) mitochondria for degradation, and loss of mitochondrial fission prevents depolarized mitochondria from being degraded ( Tanaka et al., 2010). ![]() ![]() In mammals, most fission pathways depend on dynamin-related protein 1 (Drp1), a dynamin-like GTPase recruited to fission sites on the outer mitochondrial membrane ( Itoh et al., 2013). Understanding mitochondrial biology in this compartment is critical, as axons are consistently lost before the cell body in neurodegenerative diseases that are thought to involve energy depletion ( Li et al., 2001 Scheff et al., 2007 Cheng et al., 2010). Furthermore, mitochondrial dynamics have been studied almost exclusively in the cell body of neurons in the CNS, even though the vast majority of mitochondria in many neuron types probably reside in axons ( Grafstein and Forman, 1980), and axonal mitochondria exist in unique micro-environments and have different properties from those at the cell body ( Pathak et al., 2013). Indeed, disrupted proteins that regulate mitochondrial dynamics produce selective neuronal degeneration despite being ubiquitously expressed ( Alexander et al., 2000 Züchner et al., 2004 Niemann et al., 2005). However, to understand the role of mitochondrial dynamics in PD, it is necessary to study dynamics specifically in the nigrostriatal DA neurons that degenerate. Wang et al., 2012a, b), raising the possibility that changes in mitochondrial dynamics contribute to neuronal degeneration. A number of PD-associated proteins, including α-synuclein, PINK1, parkin, DJ-1, and LRRK2, regulate the relative rates of mitochondrial fission and fusion ( Poole et al., 2008 Yang et al., 2008 Irrcher et al., 2010 Kamp et al., 2010 Tanaka et al., 2010 Nakamura et al., 2011 X. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons.ĭisruption of mitochondrial dynamics has been implicated in the pathogenesis of several neurodegenerative diseases, especially PD ( Itoh et al., 2013). However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents ( I h) is spared, despite near complete loss of their axonal mitochondria. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. Drp1 loss rapidly eliminates the DA terminals in the caudate–putamen and causes cell bodies in the midbrain to degenerate and lose α-synuclein. To study one aspect of mitochondrial dynamics-mitochondrial fission-in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. The primary analyses will be by per protocol analysis and there will also be an intention to treat analysis.Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). The statistical analysis will be performed by 2-tailed student's T-test with the platelet "mitochondria-shaping" proteins expression as the response variable. The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. Why Should I Register and Submit Results?.
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