Earliest ALS Defects Said to Start in Disparate Places

Researchers have identified some of the earliest known defects in mouse models of amyotrophic lateral sclerosis, according to two papers (1, 2) in the January 14 Journal of Neuroscience. Signs of something amiss emerge within just a few weeks of birth in an aggressive model of ALS, report researchers from the University of Queensland in St. Lucia, Australia, who observed loss of dendritic spines in upper motor neurons. In a more slowly progressing model, the first signs of pathology occurred at the other end of the motor neuron network. Scientists from the University of Montréal in Canada found that in 4-month-old mice, the perisynaptic Schwann cells that surround neuromuscular junctions had trouble supporting synapse repair. Scientists hope that by understanding these precocious pathologies, they can come up with ways to slow down ALS from the get-go. That could help people who have a genetic predisposition for the disease.

Upper Motor Neuron Dendrites Wither Early
ALS, by definition, encompasses defects in both upper and lower motor neurons, though researchers have focused mostly on the latter. Lower motor neurons are hyperexcitable (Van Zundert et al., 2008), and Matthew Fogarty in Queensland, who works with senior authors Mark Bellingham and Peter Noakes, wanted to know if upper motor neurons were as well. He examined neural signaling in mice overexpressing human SOD1 with a glycine-93-alanine mutation. Disease moves fast in this model; spinal cord motor neurons start to degenerate at 1-2 months of age, and the mice develop noticeable symptoms, such as hind leg tremor, around 90 days after birth.

Disappearing Dendrites.

By just 1 month of age, the upper motor neuron dendrites of SOD1-G93A mice (bottom) have begun to shrink, compared with wild-type brains (top). [Image courtesy of Fogarty et al., The Journal of Neuroscience, 2015]

Fogarty observed more than twice as many excitatory neural signals coming into layer V cortical upper motor neurons in brain slices from 3-week-old SOD mice than in slices from wild-type animals. The dendritic spines had already begun to shrink at that age, and in slices from 4-week-old mice, the dendrites themselves had started to shorten (see image at right). “The cells are not dying yet, but they are definitely perturbed,” Fogarty said. These dendritic abnormalities mirror some of the earliest signs of decay in lower motor neurons, commented Andrew Eisen of the University of British Columbia in Vancouver, Canada, who was not involved in the study.

Synaptic Glia Ignore Synapses in Young SOD Mice
In Montréal, first author Danielle Arbour and colleagues examined the axons of lower motor neurons, where they innervate the neuromuscular junction. This synapse relies on support from local glia called perisynaptic Schwann cells, or PSCs. These have two modes, explained senior author Richard Robitaille. Normally, the PSCs are in maintenance mode. They sense the acetylcholine released by the presynaptic terminal and release factors that make the synapse efficient and stable. In cases of mild injury, partial denervation can occur, and the PSCs shift into repair mode. They sense and react to the reduction of acetylcholine, for example by removing debris so the synapse can re-form.

Several studies have suggested that astrocytes and microglia contribute to, and perhaps even instigate, neural death in ALS (see Apr 2007 news; Boillée et al., 2006). Arbour, Robitaille, and colleagues wondered if PSCs, too, might have a role. To catch early defects, they isolated nerve-muscle connections from a slow model of ALS, i.e., mice expressing SOD1 with the glycine-37-arginine mutation. In these animals, symptoms become noticeable at about 14 months of age, middle age for a mouse. However, at 4 months, Arbour saw presynaptic terminals firing more often and more strongly. At the same time, the PSCs became highly sensitive to acetylcholine. “To our knowledge, this is the earliest persistent change reported in this mouse model,” the authors wrote. In addition, by 13-months the mice’s junctions were disorganized, an indication that denervation had begun.

Junctions Gone Wrong.

In neuromuscular junctions, presynaptic signaling (left) activates PSCs (middle), which help maintain junction structure (right). This collaboration falters in ALS. [Image courtesy of Arbour et al., The Journal of Neuroscience, 2015.]

Robitaille hypothesized that the PSCs in the ALS mice are so hyper-responsive to acetylcholine that they do not notice when its concentration drops. Then, when ALS attacks the junctions, the PSCs fail to go into repair mode and the synapse deteriorates. “The perisynaptic Schwann cells are happy campers, blind to the problems [in ALS],” Robitaille said. The researchers next want to test their hypothesis in biopsy tissue from people with the disease.

“This is the first study I know to examine the involvement of perisynaptic Schwann cells in ALS,” commented Douglas Fields of the National Institute of Child Health and Human Development in Bethesda, Maryland (see full comment below). “It makes good sense that these cells would be involved in ALS and other neuromuscular disorders … these findings open up a new avenue of research into treatments that target these unusual and important glial cells.”

Early Onset
The evidence for problems in both kinds of motor neurons mimics human disease, which in Fogarty’s view highlights the importance of the mSOD1 mouse. “If we are going to treat ALS, we need to treat both lower motor neurons and upper motor neurons,” he said. Fogarty is now testing whether upper motor neurons respond to the same treatments as lower motor neurons do.

Many neurodegenerative diseases, including Alzheimer’s and Parkinson’s, get their start years or decades before people notice any symptoms (see Jan 2015 news). “In fact, they may begin at birth,” Eisen said. “There may be many years of metabolic abnormalities before any structural change” (see Eisen et al., 2014).

But where does ALS truly start? Many scientists subscribe to the “dying back” hypothesis, whereby degeneration begins at the neuromuscular junction when motor neurons retreat from the synapse (Fischer et al., 2004). A few others, such as Eisen, prefer the “dying forward” or upper motor neuron hypothesis. “We believe ALS begins in the brain,” before spreading to lower motor neurons, he explained. Hande Ozdinler of Northwestern University Feinberg School of Medicine in Chicago agreed (see full comment below). “Many new findings show that the cortex may actually be the starting point for defects,” wrote Ozdinler, who was not involved in the study. “We should begin to appreciate the importance of cortical components of motor neuron circuitry.”

The answer is important, Eisen points out, so clinicians know where to look for those first defects. However, there is no consensus on where disease starts. Carol Milligan of Wake Forest School of Medicine in Winston-Salem, North Carolina, was not so sure that there would turn out to be one point of origin. She studies lower motor neurons of week-old SOD1-G93A mice, and told Alzforum, “We could not distinguish something happening only at one site. It is probably a continuum.”


1. Arbour D, Tremblay E, Martineau É, Julien JP, Robitaille R. Early and persistent abnormal decoding by glial cells at the neuromuscular junction in an ALS model. J Neurosci. 2015 Jan 14;35(2):688-706. [PubMed].

2. Fogarty MJ, Noakes PG, Bellingham MC. Motor Cortex Layer V Pyramidal Neurons Exhibit Dendritic Regression, Spine Loss, and Increased Synaptic Excitation in the Presymptomatic hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis. J Neurosci. 2015 Jan 14;35(2):643-7. [PubMed].

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