Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS

Comley, Laura H.; Allodi, Ilary; Nichterwitz, Susanne; Nizzardo, Monica; Simone, Carla; Corti, Stefania; Hedlund, Eva

doi:10.1016/j.neuroscience.2015.02.013

Cited by 61 publications

(91 citation statements)

References 42 publications

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“…Taken together with our current findings, these suggest that the discovery of inherent protective modifiers could be fundamental to the development of future successful combinatorial therapies [33, 60–63]. It is of particular interest to note that mitochondrial pathways have been previously highlighted as a potential disease modifier in ALS [64].…”

Section: Discussionsupporting

confidence: 57%

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Boyd

Shorrock

et al. 2017

PLoS Genet

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Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

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Section: Discussionsupporting

confidence: 57%

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Boyd

Shorrock

et al. 2017

PLoS Genet

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“…FF motor neurons also fire at higher rates than S motor neurons [6], consistent with the greater requirement for proteins necessary for synaptic function, supplied from the cell body via efficient axonal transport [62]. A recent study also demonstrated that the molecular motor dynein, which mediates both ER-Golgi transport and retrograde axonal transport, is upregulated in more vulnerable motor neurons, such as hypoglossal and spinal motor neurons, compared to oculomotor neurons, which are less vulnerable in ALS [10]. Hence these studies, together with our findings, link inhibition of ER-Golgi transport, ER stress and axonal transport, to specific vulnerability of motor neuron subtypes to neurodegeneration in ALS.…”

Section: Discussionmentioning

confidence: 63%

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

et al. 2015

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Several diverse proteins are linked genetically/pathologically to neurodegeneration in amyotrophic lateral sclerosis (ALS) including SOD1, TDP-43 and FUS. Using a variety of cellular and biochemical techniques, we demonstrate that ALS-associated mutant TDP-43, FUS and SOD1 inhibit protein transport between the endoplasmic reticulum (ER) and Golgi apparatus in neuronal cells. ER-Golgi transport was also inhibited in embryonic cortical and motor neurons obtained from a widely used animal model (SOD1(G93A) mice), validating this mechanism as an early event in disease. Each protein inhibited transport by distinct mechanisms, but each process was dependent on Rab1. Mutant TDP-43 and mutant FUS both inhibited the incorporation of secretory protein cargo into COPII vesicles as they bud from the ER, and inhibited transport from ER to the ER-Golgi intermediate (ERGIC) compartment. TDP-43 was detected on the cytoplasmic face of the ER membrane, whereas FUS was present within the ER, suggesting that transport is inhibited from the cytoplasm by mutant TDP-43, and from the ER by mutant FUS. In contrast, mutant SOD1 destabilised microtubules and inhibited transport from the ERGIC compartment to Golgi, but not from ER to ERGIC. Rab1 performs multiple roles in ER-Golgi transport, and over-expression of Rab1 restored ER-Golgi transport, and prevented ER stress, mSOD1 inclusion formation and induction of apoptosis, in cells expressing mutant TDP-43, FUS or SOD1. Rab1 also co-localised extensively with mutant TDP-43, FUS and SOD1 in neuronal cells, and Rab1 formed inclusions in motor neurons of spinal cords from sporadic ALS patients, which were positive for ubiquitinated TDP-43, implying that Rab1 is misfolded and dysfunctional in sporadic disease. These results demonstrate that ALS-mutant forms of TDP-43, FUS, and SOD1 all perturb protein transport in the early secretory pathway, between ER and Golgi compartments. These data also imply that restoring Rab1-mediated ER-Golgi transport is a novel therapeutic target in ALS.

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“…However, strong evidence suggests the MN pools involved in eye movement and pelvic sphincter control are largely spared in ALS12. Moreover, within a given MN pool, differences in vulnerability between MN subtypes (e.g.…”

mentioning

confidence: 99%

Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9

Morisaki

Niikura

Watanabe

et al. 2016

Sci Rep

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Differential vulnerability among motor neuron (MN) subtypes is a fundamental feature of amyotrophic lateral sclerosis (ALS):Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs) and skeletal muscle denervation and atrophy. However, strong evidence suggests the MN pools involved in eye movement and pelvic sphincter control are largely spared in ALS 1,2 . Moreover, within a given MN pool, differences in vulnerability between MN subtypes (e.g. alpha/gamma or fast/ slow) are a fundamental but unexplained feature of ALS. α -MNs are divided into three subtypes: fast-twitch fatigable (FF), fast-twitch fatigue-resistant (FR) and slow-twitch fatigue-resistant (S). The large-diameter low-excitability FF MNs innervate type IIB muscle fibers and degenerate early in the ALS disease course, while medium-excitability FR MNs innervating type IIA muscle fibers follow after that. The high-excitability S MNs innervating type I muscle fibers are largely resistant to degeneration and are preserved, even late in the disease course. Although molecular markers for MNs have been available for several years [3][4][5][6] , the absence of markers that distinguish FF from FR MNs has hindered analysis of the early selective degeneration of MN subtypes.

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Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS

Cited by 61 publications

References 42 publications

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9

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