Bursting the unfolded protein response accelerates axonal regeneration

Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system (PNS) is damaged. These pathological state are are associated with weakness, pain, and loss of motor and sensory control. More than 100 types of peripheral neuropathies have been identified, with distinct symptoms and prognosis classified according to the type of damage to the nerves. Injury to peripheral nerves results in disabling loss of sensory and motor functions. Damaged axons undergo degeneration distal to the injury and regeneration from the proximal stump, a fundamental process for reinnervation and functional recovery. In contrast, damage to the central nervous system (CNS) is followed by poor regeneration. In the PNS, nerve injury triggers a response known as Wallerian degeneration, characterized by axonal damage due to an increase in axoplasmic calcium, mitochondrial dysfunction and cytoskeleton breakdown (Court and Coleman, 2012). Moreover, Schwann cells (SCs) dedifferentiate to a regenerative cell phenotype, characterized by a proliferative state, the secretion of trophic factors, and the organization into a columnar cell configuration known as bands of Bungner, which guide regenerating axons. Also, SCs participate in myelin and axonal breakdown and secrete cytokines and chemokines to recruit immune cells (i.e., macrophages) into the nerve that eliminate cell debris. In addition, axotomized neurons upregulate regeneration-associated genes (RAGs) to promote axon growth. By contrast, axonal damage in the CNS is followed by limited myelin clearance and activation of astrocytes, which secrete growth-inhibitory molecules that generate an unfavorable environment for axonal regeneration. Therefore, successful axonal repair depends on intrinsic capacities of neurons and the reaction of glial cells and microenvironmental factors that modulate the regeneration process.