Subscribe to eTOC


Slowed axonal transport causes a new and rare inherited form of human motor neuron degeneration, a discovery that may accelerate understanding of more common motor neuron diseases, including amyotrophic lateral sclerosis (ALS). The discovery, by Imke Puls, MD, and colleagues at the National Institute of Neurological Disorders and Stroke (NINDS), provides support for an increasingly attractive model of motor neuron death, which holds that impaired axonal transport is a central and early event in the long slow death of these largest of neurons.

The new disorder is a slowly progressive, autosomal dominant degeneration. In contrast to ALS, which affects both upper and lower motor neurons, this new condition affects only lower motor neurons. In the Alabama family in which it was first recognized, onset is in the early adult years, and includes vocal cord paralysis, progressive facial weakness, as well as weakness and muscle atrophy of the hands. Distal leg muscles are affected later.


A genome-wide linkage study of affected and unaffected family members mapped the gene to the short arm of chromosome 2. This region contains the gene for a protein called dynactin. Dr. Puls and colleagues discovered that all affected family members had a common mutation in the dynactin gene not shared by any unaffected members or 200 controls.

“This gene turned out to be interesting,” said Kenneth Fischbeck, MD, “because it connects the field of motor neuron disease research to the field of motor neuron research.” Dr. Fischbeck is head of the NINDS lab where Dr. Puls is a research fellow and is a coauthor on the study, which appeared in the April issue of Nature Genetics(2003;33(4):455-456).

The connection hinges on dynactin's role in facilitating axonal transport. “Motor neurons are particularly dependent on axonal transport,” said Dr. Fischbeck, due to the enormous length of their axons. Proteins and other cell components manufactured in the cell body must be moved to the axon terminal, as much as a meter away in some cases. Growth factors and other signals from the periphery undergo retrograde transport, from the terminal to the nucleus.


A large protein complex called dynein is one of the principal engines of axonal transport – with vesicles or other cargo lashed to it, dynein motors along the cell's microtubule highway system. Helping connect dynein to the microtubules is the job of dynactin.

Dynactin was discovered in 1991, and its role in transport was identified in 1997. In the same year, a dynactin defect was linked to neurodegeneration in the fly, and in 2002, Erika Holzbaur, PhD, and colleagues at the University of Pennsylvania showed that mice overexpressing a dynactin subunit suffered a significant impairment in retrograde axonal transport and developed a delayed progressive motor neuron disease.

The mutation in Dr. Puls's patients is in a different dynactin subunit, but its effect appears to be similar – a decreased ability of dynein to bind to microtubules, leading to motor neuron degeneration. “The substantial but limited reduction in the affinity of [the subunit] for microtubules is consistent with the late onset and relatively mild disease progression observed in this kindred,” wrote Dr. Puls.


Teepu Siddique, MD, at Northwestern University in Chicago and a leading researcher in ALS genetics, noted that, while this disease differs from ALS in some important respects, it may have a lot to offer in the search for the causes of many types of neuron degeneration. “This is a very elegant demonstration that rare experiments of nature can point to crucial areas of neurobiology that should become the focus of investigation,” he said.

The focus on disrupted transport has become increasingly sharp in recent years. “A motor neuron has to make contact with muscle, and signals from the muscle have to get up the axon,” Dr. Fischbeck said. If they do not, he said, the neuron dies. Clogging this vital supply line between cell body and axon terminal leads to “neuronal strangulation.”

In addition to the discovery of the dynactin mutations, other recent findings also point toward a transport defect as central to motor neuron pathology. Some forms of familial juvenile ALS, as well as primary lateral sclerosis, which affect only upper motor neurons, are caused by mutation of alsin. The structure of the alsin protein suggests it may facilitate vesicle transport. The peripheral neuropathy of Charcot-Marie-Tooth disease type 2 is due to a defect in another molecular transport motor, kinesin.


This lends credence to one particular theory of pathogenesis in the most commonly inherited form of ALS. About 10 percent of all ALS cases are familial, and of these, approximately 20 percent are due to dominant mutations in Cu/Zn superoxide dismutase 1(SOD1), discovered in 1993. While early hypotheses suggested either under- or overactivity of SOD1 might lead directly to excitotoxic death, experiments have not lent much support. In 1999, Donald Cleveland, PhD, of the University of California-San Diego showed that in SOD1-mutant mice, slowed axonal transport was a very early event, preceding overt motor symptoms by months.

Despite these provocative connections, Dr. Siddique, whose group has the largest number of familial ALS specimens available for genetic testing, said he does not expect dynactin mutations to account for many of the non-SOD1 cases. “We have to look at the entire system,” he cautioned, and not just at transport.


Sharon Hesterlee, PhD, concurs. Dr. Hesterlee, Research Director for the Muscular Dystrophy Association, which helped fund the dynactin study, likened untangling the puzzle of ALS to reconstructing a disaster scene, but without the black box recorder.


Dr. Teepu Siddique

“There are all these pieces of the puzzle, and it's very hard to establish cause and effect.” Much evidence points strongly toward transport defects, she said, “but it doesn't mean that's the cause. It might be the final common pathway. We don't understand the story as well upstream.”

Another strong model of ALS implicates glutamate dysregulation, and so far no evidence links excess glutamate to transport failure. “I couldn't even guess how these fit together,” said Dr. Hesterlee.

Where all this leaves the pathogenesis of sporadic ALS also remains a mystery. Dr. Siddique's group is undertaking whole-genome screening of sporadic patients to determine if there is a hidden genetic predisposition in these patients.

“Clearly people are set up by their genes,” he said, allowing the environment to knock them down, so to speak. Will any of these set the stage for development of a transport defect? It's too soon to tell. And while finding a common point of intersection between the causes of sporadic and familial ALS would be gratifying, he said, “We have to be led by our experiments, rather than wishful thinking. But of course one hopes.”