Targeting ER stress pathways in neurodegenerative diseases

Multiple Sclerosis (MS) is an inflammatory, autoimmune disease characterized by degeneration of myelin sheaths surrounding neurons in the Central Nervous System (CNS), resulting in impaired neuronal signaling in the brain and spinal cord. This common immune-mediated demyelinating disease affects one in 1000 people.

Considerable research has been invested into understanding how the cellular components in the CNS responsible for myelination, oligodendrocytes (OLs), are compromised during MS disease progression. Dr. Brian Popko from the University of Chicago has studied the role of OL apoptosis in initiating inflammatory immune responses in MS as well as how OLs contribute to disease progression. A focus on enhancing OL cell viability could provide a target for therapeutic intervention in preventing these inflammatory, autoimmune responses in MS. More specifically, Popko investigated how the endoplasmic reticulum (ER) stress pathway in OLs could be a target for protection. Activation of ER stress leads to a series of chemical cascades that result in eIF2α phosphorylation, which shifts the cell to a protective state. Popko provides evidence that prolonging this protective state, by attenuating the dephosphorylation of eIF2α, can prevent several MS pathologies. Administration of a drug called guanabenz acts in this fashion to ultimately promote myelination of CNS, prolong disease onset of experiemental models of MS, and prevent MS relapse.

This novel drug guanabenz has also been studied as a therapeutic intervention for other neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS). ALS is characterized as a CNS neurodegenerative disease resulting in cell death of motor neurons in the motor cortex, brain stem, and spinal cord¹. The mechanisms behind ALS are poorly understood, but researchers have associated the ER stress pathway with neuronal cell death observed in ALS pathogenesis¹. Similar to Popko’s use of guanabenz in promoting continuous eIF2α phosphorylation to protect against MS, Jiang et al. investigated whether this drug could also serve a protective role in ALS¹. Using a mouse ALS experimental model, Jiang et. al discovered that guanabenz administration lead to a delayed disease onset, decreased motor neuron loss, and decreased pro-apoptotic pathways¹. These results show that guanabenz is sufficient in preventing ALS pathologies.

Collectively, the findings from Popko and Jiang et. al underscore the importance of ER stress pathways underlying neurodegenerative diseases. The administration of guanabenz was capable of reducing several MS and ALS pathologies, suggesting that this drug may be a potential therapeutic for neurodegenerative diseases in the future.

References:

1. Jiang H.-G. et al. Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. Neuroscience (2014), http://dx.doi.org/10.1016/j.neuroscience.2014.03.047