Dataset Information

Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal.

ABSTRACT: Impairment of mitochondrial transport has long been implicated in the pathogenesis of neuropathy and neurodegeneration. However, the role of mitochondria in stabilizing motor nerve terminals at neuromuscular junction (NMJ) remains unclear. We previously demonstrated that mice lacking the antioxidant enzyme, superoxide dismutase-1 (Sod1-/-), develop progressive NMJ denervation. This was rescued by expression of SOD1 exclusively in the mitochondrial intermembrane space (MitoSOD1/Sod1-/-), suggesting that oxidative stress within mitochondria drives denervation in these animals. However, we also observed reduced mitochondrial density in Sod1-/- motor axons in vitro. To investigate the relationship between mitochondrial density and NMJ innervation in vivo, we crossed Sod1-/- mice with the fluorescent reporter strains Thy1-YFP and Thy1-mitoCFP. We identified an age-dependent loss of mitochondria at motor nerve terminals in Sod1-/- mice, that closely correlated with NMJ denervation, and was rescued by MitoSOD1 expression. To test whether augmenting mitochondrial transport rescues Sod1-/- axons, we generated transgenic mice overexpressing the mitochondrial cargo adaptor, Miro1. This led to a partial rescue of mitochondrial density at motor nerve terminals by 12?months of age, but was insufficient to prevent denervation. These findings suggest that loss of mitochondria in the distal motor axon may contribute to denervation in Sod1-/- mice, perhaps via loss of key mitochondrial functions such as calcium buffering and/or energy production.

SUBMITTER: Hayes LR

PROVIDER: S-EPMC6588488 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal.

Hayes Lindsey R LR Asress Seneshaw A SA Li Yingjie Y Galkin Alexander A Stepanova Anna A Kawamata Hibiki H Manfredi Giovanni G Glass Jonathan D JD

Experimental neurology 20190510

Impairment of mitochondrial transport has long been implicated in the pathogenesis of neuropathy and neurodegeneration. However, the role of mitochondria in stabilizing motor nerve terminals at neuromuscular junction (NMJ) remains unclear. We previously demonstrated that mice lacking the antioxidant enzyme, superoxide dismutase-1 (Sod1-/-), develop progressive NMJ denervation. This was rescued by expression of SOD1 exclusively in the mitochondrial intermembrane space (MitoSOD1/Sod1-/-), suggesti ...[more]

PMID: 31082391

Similar Datasets

Project description:Clinical effects of anti-cholinergic drugs implicate cholinergic systems alterations in the pathophysiology of some cardinal motor impairments in Parkinson's disease. The topography of affected cholinergic systems deficits and motor domain specificity are poorly understood. Parkinson's disease patients (n = 108) underwent clinical and motor assessment and vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol PET imaging. Volumes-of-interest-based analyses included detailed thalamic and cerebellar parcellations. Successful PET sampling for most of the small-sized parcellations was available in 88 patients. A data-driven approach, stepwise regression using the forward selection method, was used to identify cholinergic brain regions associating with cardinal domain-specific motor ratings. Regressions with motor domain scores for model-selected regions followed by confounder analysis for effects of age of onset, duration of motor disease and levodopa equivalent dose were performed. Among 7 model-derived regions associating with postural instability and gait difficulties domain scores three retained significance in confounder variable analysis: medial geniculate nucleus (standardized β = -0.34, t = -3.78, P = 0.0003), lateral geniculate nucleus (β = -0.32, t = -3.4, P = 0.001) and entorhinal cortex (β = -0.23, t = -2.6, P = 0.011). A sub-analysis of non-episodic postural instability and gait difficulties scores demonstrated significant effects of the medial geniculate nucleus, entorhinal cortex and globus pallidus pars interna. Among 6 tremor domain model-selected regions two regions retained significance in confounder variable analysis: cerebellar vermis section of lobule VIIIb (β = -0.22, t = -2.4, P = 0.021) and the putamen (β = -0.23, t = -2.3, P = 0.024). None of the three model-selected variables for the rigidity domain survived confounder analysis. Two out of the four model-selected regions for the distal limb bradykinesia domain survived confounder analysis: globus pallidus pars externa (β = 0.36, t = 3.9, P = 0.0097) and the paracentral lobule (β = 0.26, t = 2.5, P = 0.013). Emphasizing the utility of a systems-network conception of the pathophysiology of Parkinson's disease cardinal motor features, our results are consistent with specific deficits in basal forebrain corticopetal, peduncupontine-laterodorsal tegmental complex, and medial vestibular nucleus cholinergic pathways, against the background of nigrostriatal dopaminergic deficits, contributing significantly to postural instability, gait difficulties, tremor and distal limb bradykinesia cardinal motor features of Parkinson's disease. Our results suggest significant and distinct consequences of degeneration of cholinergic peduncupontine-laterodorsal tegmental complex afferents to both segments of the globus pallidus. Non-specific regional cholinergic nerve terminal associations with rigidity scores likely reflect more complex multifactorial signalling mechanisms with smaller contributions from cholinergic pathways.

Dataset Information

Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal.

Publications

Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets