Morphometric Comparison of the Vulnerability of Peripheral Motor and Sensory Neurons in Amyotrophic Lateral Sclerosis

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107

Male mice with inactivated liver X receptor (LXR) β suffer from adult-onset motor neuron degeneration. By 7 months of age, motor coordination is impaired, and this condition is associated with lipid accumulation and loss of motor neurons in the spinal cord, together with axonal atrophy and astrogliosis. Several of these features are reminiscent of the neuropathological signs of chronic motor neuron disease such as amyotrophic lateral sclerosis. Because the LXRs are important for cholesterol and lipid metabolism, we speculate that absence of LXRβ leads to pathological accumulation of sterols and lipids that may themselves be neurotoxic or may modulate intracellular pathways and thereby predispose motor neurons to degeneration.

Section: Discussionmentioning

confidence: 63%

Inactivation of liver X receptor β leads to adult-onset motor neuron degeneration in male mice

Andersson

Gustafsson

Warner

et al. 2005

152

107

“…In this study we use a combination of three molecular markers of γ-MNs-the Hb9::GFP transgene, NeuN, and the GDNF receptor reporter Gfrα1-TLZ-to demonstrate complete and selective sparing of γ-MNs even at late stages of disease in three unrelated transgenic models of ALS respectively expressing mutant SOD1 G93A , TDP-43 A315T , or FUS P525L . Together, these independent markers enable us to identify γ-MN cell bodies in the ventral horn of the spinal cord of these mutants and to address the possibility that the loss of individual markers and changes in MN morphology (29) in the mutant mice may have led to the misidentification of shrunken α-MNs as γ-Μs, a criticism that limited several previous studies suggesting γ-MN sparing in ALS patients and in the SOD1 mouse model (22)(23)(24)(25)(26). Moreover, we demonstrate that the majority of NMJs on muscle spindles of the TA muscle remain innervated at end stage, consistent with the complete sparing of γ fusimotor axons that contact ∼90% of intrafusal NMJs (17).…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have shown that in ALS patients and mouse models of disease the average soma size of surviving MNs is significantly reduced. This observation has been interpreted by many to suggest the selective resistance of γ-MNs, whereas others explain the finding as a result of cell shrinkage that precedes cell body loss (22)(23)(24)(25)(26)(27)29). To distinguish between these possibilities, we took advantage of our previous studies in which we identified γ-MNs by the absence of NeuN staining and failure to express the Hb9::GFP transgene (17,18 (Fig.…”

Section: γ-Mns Are Selectively Spared At the End Stage Of Disease In mentioning

confidence: 99%

“…In several prior studies the absence of selective markers of γ-MN identity and the reliance on size criteria alone made it difficult to assess the role of γ-MNs in ALS patients and in mouse models of disease (22)(23)(24)(25)(26)(27). This uncertainty left open several questions about the role of γ-MNs in ALS, including whether a decrease in the average soma size of α-MNs in the disease led to a misidentification of small α-MNs as γ-MNs.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS

Lalancette–Hébert

Sharma

Lyashchenko

et al. 2016

106

The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (I A ) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced I A activation by targeted reduction of γ-MNs in SOD1G93A mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.ALS | motor neuron disease | gamma motor neuron | fusimotor A myotrophic lateral sclerosis (ALS) is a fatal disorder characterized by selective motor neuron (MN) degeneration in the brain and spinal cord (1). Not all MN subtypes are equally vulnerable in ALS, and specific subpopulations of MNs, including neurons in the oculomotor and Onuf's nuclei, are preserved even at late stages of disease (2-8). The sparing of these motor pools in ALS is complete, but within the motor pools that are affected the degree to which distinct functional subtypes of MNs are vulnerable varies: fast-fatigable motor neurons are the first to degenerate in ALS patients (9) and in mutant SOD1 mice (10, 11), followed by fatigue-resistant motor units, whereas slow motor units are preserved until late in the course of the disease (12). The reason for the selective vulnerability of distinct subpopulations of MNs in ALS is not known, but factors that determine the unique features of individual MN subtypes, including their size, morphology, and membrane properties, may play a role. In addition, the factors that influence MN vulnerability in ALS may relate to the organization and function of synaptic inputs on each MN subtype that regulate MN activity and control motor output. How the connectivity of MNs within complex motor circuits influences their relative vulnerability in ALS is not known.Extraocular muscles composed of multiple (fast-, intermediate-, and slow-twitch) fiber types (13) and innervated by ALS

“…Indeed, aberrant accumulations of NFs are a common pathological hallmark in both sporadic and familial ALS (13)(14)(15) as well as in some mutant SOD1 mouse models (5,16,17). NFs are obligate heteropolymers of NF light (NF-L), NF medium (NF-M), and NF heavy (NF-H) subunits (18,19) and are the most abundant structural components of large myelinated axons, the neurons most at risk in human ALS (20) and mutant SOD1 mouse models (7). The large tail domains of NF-M and NF-H are nearly stochiometrically phosphorylated and are responsible for assembly of a 3D, crosslinked axoplasm that supports acquisition of normal axonal caliber (21).…”

mentioning

confidence: 99%

Altered axonal architecture by removal of the heavily phosphorylated neurofilament tail domains strongly slows superoxide dismutase 1 mutant-mediated ALS

Lobsiger

Garcia

Ward

et al. 2005

Eliminating assembled neurofilaments (NFs) from axons or misaccumulating NFs in motor neuron cell bodies strongly slows disease in mouse models of mutant superoxide dismutase 1 (SOD1)-induced amyotrophic lateral sclerosis. One proposal for how reducing axonal NFs can increase survival is that the multiphosphorylated tail domains of the two larger NF subunits act in motor neuron cell bodies as phosphorylation sinks where they mitigate cyclin-dependent kinase 5 dysregulation induced by mutant SOD1. Elimination by gene targeting in mice of the NF medium and NF heavy tail domains and their 58 known phosphorylation sites accelerates aberrant phosphorylation of other neuronal substrates while leaving overall NF content unaltered. However, disease onset is significantly delayed and survival is extended, inconsistent with the ameliorative property of altered NF content protecting by serving as substrates for dysregulation of any NF kinase. Moreover, at comparable disease stages significantly more surviving motor neurons and axons were found in SOD1 mutant mice deleted in the NF tails than in similar mice with wild-type NFs. This finding supports noncell autonomous toxicity in SOD1 mutant-mediated amyotrophic lateral sclerosis: removal of the NF tails slows damage developed directly within motor neurons, but SOD1 mutant damage within nonneuronal supporting cells reduces motor neuron functionality.axonal transport ͉ axonal cytoskeleton ͉ cyclin-dependent kinase 5