GDNF to the rescue: GDNF delivery effects on motor neurons and nerves, and muscle re-innervation after peripheral nerve injuries

Abstract

Peripheral nerve injuries commonly occur due to trauma, like a traffic accident. Peripheral nerves get severed, causing motor neuron death and potential muscle atrophy. The current golden standard to treat peripheral nerve lesions, especially lesions with large (≥ 3 cm) nerve gaps, is the use of a nerve autograft or reimplantation in cases where nerve root avulsions occur. If not tended early, degeneration of motor neurons and loss of axon regeneration can occur, leading to loss of function. Although surgical procedures exist, patients often do not fully recover, and quality of life deteriorates. Peripheral nerves have limited regeneration, and it is usually mediated by Schwann cells and neurotrophic factors, like glial cell line-derived neurotrophic factor, as seen in Wallerian degeneration. Glial cell line-derived neurotrophic factor is a neurotrophic factor known to promote motor neuron survival and neurite outgrowth. Glial cell line-derived neurotrophic factor is upregulated in different forms of nerve injuries like axotomy, sciatic nerve crush, and compression, thus creating great interest to explore this protein as a potential treatment for peripheral nerve injuries. Exogenous glial cell line-derived neurotrophic factor has shown positive effects in regeneration and functional recovery when applied in experimental models of peripheral nerve injuries. In this review, we discuss the mechanism of repair provided by Schwann cells and upregulation of glial cell line-derived neurotrophic factor, the latest findings on the effects of glial cell line-derived neurotrophic factor in different types of peripheral nerve injuries, delivery systems, and complementary treatments (electrical muscle stimulation and exercise). Understanding and overcoming the challenges of proper timing and glial cell line-derived neurotrophic factor delivery is paramount to creating novel treatments to tend to peripheral nerve injuries to improve patients’ quality of life.

Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-related disease risk and novel therapeutic targets

“…For example, the sole colocalising cis -eQTL signal (rs62360376) for GDNF was in skeletal muscle from GTEx, where, according to the Human Protein Atlas 20 , GDNF mRNA is enriched (i.e., tissue-enhanced) relative to other human tissues. GDNF production by skeletal muscle is responsive to physical activity, and has been shown to be a survival factor for peripheral motor neurons 21, 22 . Similarly, there were several colocalising cis -eQTLs from the eQTL Catalogue highlighting specific cell types, including one for TNFRSF9 (rs1776354) in Natural Killer Cells, and another for IL18R1 (rs2270297) in Th17 memory cells.…”

Exogenous GDNF promotes peripheral facial nerve regeneration in rats through the PI3K/AKT/mTOR signaling pathway

“…The most effective neurotrophic factor for stimulating neuronal growth in vitro is GDNF, 24 but it is only sparingly produced in neuronal tissues. Instead, the majority of GDNF is produced and secreted by peripheral target tissues that are innervated by it, and it is then transported retrogradely to the motoneurons along the axon by uptaking through the nerve endings 25 . Therefore, 3 days after surgery, GDNF could not be retrogradely transported to neurons via axons in the rat facial nerve, and the intensity of GDNF immunofluorescence in facial motoneurons of all groups except the GDNF group decreased to varying degrees.…”

Utilization of the Rat Tibial Nerve Transection Model to Evaluate Cellular and Molecular Mechanisms Underpinning Denervation-Mediated Muscle Injury

“…If reinnervation is delayed, however, the muscle's reparative ability is exhausted, and myofibers are replaced by fibrosis and fat [6][7][8][9][10]. Several neurotrophic factors, such as glial-cell-line-derived neurotrophic factor (GDNF), are produced by cells within the injured nerve (e.g., neurons and Schwann cells) and muscle [11,12], promoting nerve regeneration from the proximal injury site, but the rate is slow (at 1 to 3 mm/day [12][13][14][15]). Thus, following injury in the brachial plexus or upper 2 of 19 arm in an adult, the regenerating nerve can take 2 years to reach the forearm and hand muscles, at which time, the atrophied muscles are replaced by fibrous connective tissue.…”