The Complex Work of Proteases and Secretases in Wallerian Degeneration: Beyond Neuregulin-1

Pellegatta, Marta; Taveggia, Carla

doi:10.3389/fncel.2019.00093

Cited by 30 publications

(21 citation statements)

References 190 publications

(254 reference statements)

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“…The calcium triggers endogenous proteolysis and the degeneration of the axonal cytoskeleton. This is followed by fragmentation, disintegration, and finally, the phagocytosis of the axons and their myelin, initially by the SCs themselves [11][12][13][14]. Thereafter, the macrophages that enter through the leaky blood-brain barrier, play the predominant role in the Wallerian degeneration [15][16][17][18], the duration of which is surprisingly long, up to a month in rats for example [17,19].…”

Section: Wallerian Degenerationmentioning

confidence: 99%

Peripheral Nerve Regeneration and Muscle Reinnervation

Gordon

2020

IJMS

221

144

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Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to “find” their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.

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Section: Wallerian Degenerationmentioning

confidence: 99%

Peripheral Nerve Regeneration and Muscle Reinnervation

Gordon

2020

IJMS

221

144

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“…There has been recent interest in the role of sheddases, such as BACE1, members of the A disintegrin and metalloproteinase (ADAM) family, and gamma secretases in the process of nerve regeneration. This topic has been comprehensively detailed in the following review [ 33 ]. Sheddases are known to be regulators of Schwann cells, particularly in the context of myelination.…”

Section: Events Following Peripheral Nerve Injurymentioning

confidence: 99%

The influence of BACE1 on macrophage recruitment and activity in the injured peripheral nerve

Fissel

Farah

2021

J Neuroinflammation

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Following peripheral nerve injury, multiple cell types, including axons, Schwann cells, and macrophages, coordinate to promote nerve regeneration. However, this capacity for repair is limited, particularly in older populations, and current treatments are insufficient. A critical component of the regeneration response is the network of cell-to-cell signaling in the injured nerve microenvironment. Sheddases are expressed in the peripheral nerve and play a role in the regulation if this cell-to-cell signaling through cleavage of transmembrane proteins, enabling the regulation of multiple pathways through cis- and trans-cellular regulatory mechanisms. Enhanced axonal regeneration has been observed in mice with deletion of the sheddase beta-secretase (BACE1), a transmembrane aspartyl protease that has been studied in the context of Alzheimer’s disease. BACE1 knockout (KO) mice display enhanced macrophage recruitment and activity following nerve injury, although it is unclear whether this plays a role in driving the enhanced axonal regeneration. Further, it is unknown by what mechanism(s) BACE1 increases macrophage recruitment and activity. BACE1 has many substrates, several of which are known to have immunomodulatory activity. This review will discuss current knowledge of the role of BACE1 and other sheddases in peripheral nerve regeneration and outline known immunomodulatory BACE1 substrates and what potential roles they could play in peripheral nerve regeneration. Currently, the literature suggests that BACE1 and substrates that are expressed by neurons and Schwann cells are likely to be more important for this process than those expressed by macrophages. More broadly, BACE1 may play a role as an effector of immunomodulation beyond the peripheral nerve.

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“…During cancer invasion, the nerve structure is altered and Schwann cells may have a role in promoting cancer cells’ adhesion to axons and thus their invasiveness (123). This phenomenon probably occurs because Schwann cells are plastic cells, as demonstrated by the analysis of the processes regulating nerve regeneration after injury [120].…”

Section: Nerve—cancer Microenvironmentmentioning

confidence: 99%

“…Matrix Metalloproteinases (MMPs) are proteolytic enzymes required for the degradation of extracellular matrix; several MMPs are implicated in PDAC [214], in particular high levels of MMP–2/9 in PDAC correlate with metastasis and poor prognosis [215,216,217,218]. MMP–2/9 are also expressed in Schwann Cells, where they facilitate neuritic growth and regeneration after injury [120,219] and cleave beta dystroglycan, altering the structure of the axonal compartments [220].…”

Section: Molecules and Pathways Involved In Pnimentioning

confidence: 99%

Nerves and Pancreatic Cancer: New Insights into A Dangerous Relationship

Gasparini

Pellegatta

Crippa

et al. 2019

Cancers

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Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer—particularly in pancreatic ductal adenocarcinoma (PDAC)—PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously (“present” or “absent”). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC.

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The Complex Work of Proteases and Secretases in Wallerian Degeneration: Beyond Neuregulin-1

Cited by 30 publications

References 190 publications

Peripheral Nerve Regeneration and Muscle Reinnervation

Peripheral Nerve Regeneration and Muscle Reinnervation

The influence of BACE1 on macrophage recruitment and activity in the injured peripheral nerve

Nerves and Pancreatic Cancer: New Insights into A Dangerous Relationship

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