Elisabetta Babetto, PhD, and Bogdan K. Beirowski, MD, PhD

Elisabetta Babetto, PhD, left, and Bogdan K. Beirowski, MD, PhD, are studying axonal degeneration in neurological disorders such as Charcot-Marie-Tooth disease and Guillain-Barré syndrome.

Axonal Degeneration Focus of Multiple Studies at HJKRI

Published August 3, 2018

Researchers at the Hunter James Kelly Research Institute (HJKRI) have been awarded a pair of grants for the investigation of mechanisms underlying axonal degeneration in certain neurological disorders.

“Because glial abnormalities associated to axon loss can be observed in many other neurodegenerative conditions, this approach has the potential for wide-ranging therapeutic impact.”
Assistant professor of biochemistry

Axons are the longest cellular projections of neurons relaying electrical and biochemical signals in nerves and white-matter tracts of the nervous system.

As such, they are critical for neuronal wiring and transport of neuronal maintenance signals.

Degeneration of long axons is a hallmark in a wide range of neuromuscular conditions including Charcot-Marie-Tooth (CMT) disease, Friedreich’s ataxia, amyotrophic lateral sclerosis, spinal muscular atrophy, Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP).

‘Underlying Mechanisms Poorly Understood’

A grant funded by the Muscular Dystrophy Association (MDA) was awarded to Bogdan K. Beirowski, MD, PhD, assistant professor of biochemistry.

Elisabetta Babetto, PhD, senior research scientist in biochemistry and research assistant professor of pharmacology and toxicology in the HJKRI, was awarded a grant funded by GBS/CIDP Foundation International.

Beirowski is principal investigator on the MDA-funded project titled “Deciphering Metabolic Support of Axons by LKB1 Signaling in Schwann Cells.”

He notes that axonal losses reduce neuronal connectivity and lead to the most debilitating symptoms in many neurological disorders.

“However, the underlying mechanisms are poorly understood,” says Beirowski, principal investigator at the HJKRI. ”In CMT neuropathies, it remains unknown how malfunction in Schwann cells (SCs), the myelinating cells of the peripheral nervous system, results in axon degeneration.”

“Many neuroscientists consider the decay of the myelin sheaths, formed by SCs, as etiological for axon damage, but this is only half of the truth,” he adds. “A perhaps more ancestral function of SCs is the metabolic support of axons they associate with, and this function may be perturbed in neuropathies.”

Focus on Previously ID’d Metabolic Pathway

Indeed, they have previously shown that the disruption of metabolic homeostasis by elimination of the metabolic master regulator liver kinase B1 (LKB1) in SCs of mutant mice results in progressive axon degeneration that recapitulates key features of axonopathy in disease.

Using genetic mouse models in their laboratory, along with the application of novel technologies to study SC mitochondrial and lipid metabolism, the researchers intend to identify glial metabolic pathways important for regulation of axon integrity.

“Moreover, we intend to investigate if abnormalities in such pathways may contribute to nerve damage and axon demise in CMT neuropathy models,” Beirowski says.

The project’s specific aims are to:

  • identify differentially regulated signaling downstream of LKB1 that leads to axon demise
  • determine downstream mitochondrial and lipid alterations in SCs associated with axon destabilization
  • study LKB1 signaling abnormalities in established mouse models for the most common CMT forms

Wide-Ranging Therapeutic Impact Potential

If specific metabolic lesions can be identified in SCs that are relevant to axon maintenance, treatment by manipulation of the pathways in glia may possibly ameliorate axon damage in patients suffering from diseases such as CMT, Beirowski says.

“Because glial abnormalities associated to axon loss can be observed in many other neurodegenerative conditions, this approach has the potential for wide-ranging therapeutic impact,” he adds.

Babetto is a co-investigator on the study. Gunes E. Atilla-Gokcumen, PhD, J. Solo assistant professor of chemistry, is also a co-investigator.

Progressive Axon Demise Implicated in GBS

Axonal degeneration also accounts for the most debilitating clinical symptoms of Guillain-Barré syndrome (GBS), including loss of movement and sensation — and in 20 to 30 percent of GBS cases — life-threatening respiratory failure.

Babetto is principal investigator on a study titled “Targeting Wallerian-Like Degeneration in GBS Mouse Models,” funded by GBS/CIDP Foundation International.

Progressive axon demise is a centerpiece of acute motor axonal neuropathy (AMAN) and also occurs in acute inflammatory demyelinating neuropathy and Miller Fisher syndrome (MFS), Babetto says.

“Despite causing the most debilitating symptoms, axon degeneration is not considered as a therapeutic target in these conditions because the underlying mechanisms remain obscure,” she says.

Similarities to Wallerian Degeneration

The researchers hypothesize that axon degeneration in GBS is regulated by molecular mechanisms akin to those orchestrating Wallerian degeneration (WD), a conserved self-destruction program of injured axons.

“Since WD can be blocked by suppressing recently discovered key components that promote this program, we hypothesize that axon demise in GBS can be ameliorated through similar interventions,” Babetto says.

The Phr1 E3 ubiquitin ligase (Phr1) and the sterile alpha and TIR motif-containing protein 1 (SARM1) are two central elements of the WD pathway.

The researchers plan to study axon dysfunction and structural axon integrity in established mouse models of AMAN and MFS, in both of which the central components (SARM1 or Phr1) have been inactivated.

University of Glasgow Collaborators Involved

The project’s specific aims are to test the hypotheses that:

  • Phr1 or SARM1 promote axon and synapse degeneration in a mouse model of AMAN
  • Phr1 or SARM1 promote axon and synapse degeneration in a mouse model of MFS

“This project has the potential to lead to important mechanistic insights for future development of therapies aimed at axon protection in GBS,” Babetto says.

Beirowski is a collaborator on the project and Nicholas J. Silvestri, MD, clinical associate professor of neurology, is a consultant.

Other collaborators on the project are from the University of Glasgow College of Medical, Veterinary and Life Sciences Institute of Infection, Immunity and Inflammation.