Duke University Medical Center Release: Discovery Of A Gene Function Sheds Light On New Treatment Strategies For Amyotrophic Lateral Sclerosis (ALS)

A team of scientists led by Dr. Paulo A. Ferreira at Duke University Medical Center and whose work was supported by the National Institutes of Health, has found evidence that derailing the transport of certain receptors that carry cargoes from and to the nucleus of motor neurons causes motor neuron disease in mice that recapitulates cardinal features of amyotrophic lateral sclerosis (ALS).

ALS, which is also known as Lou Gehrig’s disease, is a progressive and fatal neurodegenerative disease. ALS is transmitted in families or develops sporadically in patients. Despite decades of work and strong developments in understanding ALS, there is presently no cure for ALS and other motor neuron diseases.

The control of the flow of information (e.g. signals) by factors to and from the nucleus is critical to the execution of a myriad of tasks in neurons that are programmed in the nucleus. The nucleus is the command center of any cell where all genetic information is stored. Prior studies have hinted that the shuttling of cargoes from and to the nucleus of motor neurons were deregulated in various forms of ALS and that modulators of these cargoes were strong modifiers of disease features linked to ALS.

However, evidence was lacking to this date that regulators of shuttling of cargoes between the nuclear and cytosolic compartments of motor neurons cause ALS syndromes. The Ferreira’s team has been investigating the functions of a multifunctional factor, called Ran-binding protein 2 (Ranbp2), in neurons and several diseases for several years.

The Ranbp2 is present at the gates of the nuclear envelope, which seals the nucleus from other cellular compartments. Ranbp2 controls and coordinates the flow of biological material (e.g., proteins and RNA) at the nuclear gates by regulating factors that participate in a series of multistep and complex events. These events underpin the handover of cargoes between receptors and accessory factors exported from or imported to the nucleus. The tight coordination of these events is critical to the function of motor neurons, because of the very large size and extreme compartmentation of these specialized neurons.

The Ferreira laboratory developed the first mouse model which presents an impairment of the shuttling of selective cargoes between the nuclear and cytoplasmic compartments of motor neurons by engineering the removal of Ranbp2 from these neurons. The removal of Ranbp2 from motor neurons causes progressive motor deficits and culminates in hallmark behavioral and motor features of ALS, such as paralysis, dysphagia, respiratory distress and ultimately, the premature death of mice.

The Ferreira’s team has also found that removal of Ranbp2 from motor neurons disrupts the localization and regulation of several factors that control nuclear export and import, and inflammatory signaling between neurons and supporting glial cells. “This research defines the role of a critical molecular pathway (i.e., nuclear-cytoplasmic trafficking) in motor neuron functions and disease, and multiple entry points to alternative therapeutics for diseases, such as ALS” said Dr. Ferreira.

The Ferreira’s group has already found and reported small molecules that control specific activities of Ranbp2 and that prevent the accumulation of toxic substrates causing ALS. The generation of mouse models with ALS syndromes will be an important step to understand in greater depth the functions of motor neurons and diseases affecting these neurons. These mouse models will also allow the testing of novel treatment strategies that aim at suppressing the accumulation of toxic substrates and ameliorate or cure syndromes linked to ALS. The new findings are available electronically ahead of print and as open access in Disease Models & Mechanisms (doi:10.1242/dmm.027730)

Journal Reference:

1. Kyoung-in Cho, Dosuk Yoon, Sunny Qiu, Zachary Danziger, Warren M. Grill, William C. Wetsel, Paulo A. Ferreira (2017) Loss of Ranbp2 in motor neurons causes the disruption of nucleocytoplasmic and chemokine signaling and proteostasis of hnRNPH3 and Mmp28, and the development of amyotrophic lateral sclerosis (ALS)-like syndromes. Disease Models & Mechanisms; [Epub ahead of print]: doi:10.1242/dmm.027730; published online 18 January 2017

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