Peptidylarginine deiminases and extracellular vesicles: prospective drug targets and biomarkers in central nervous system diseases and repair

Peptidylarginine deiminases are a family of calcium-activated enzymes with multifaceted roles in physiological and pathological processes,including in the central nervous system.Peptidylarginine deiminases cause post-translational deimination/citrullination,leading to changes in structure and function of a wide range of target proteins.Deimination can facilitate protein moonlighting,modify protein-protein interaction,cause protein dysfunction and induce inflammatory responses.Peptidylarginine deiminases also regulate the biogenesis of extracellular vesicles,which play important roles in cellular communication through transfer of extracellular vesicle-cargo,e.g.,proteins and genetic material.Both peptidylarginine deiminases and extracellular vesicles are linked to a number of pathologies,including in the central nervous system,and their modulation with pharmacological peptidylarginine deiminase inhibitors have shown great promise in several in vitro and in vivo central nervous system disease models.Furthermore,extracellular vesicles derived from mesenchymal stem cells have been assessed for their therapeutic application in central nervous system injury.As circulating extracellular vesicles can be used as non-invasive liquid biopsies,their specific cargo-signatures(including deiminated proteins and microRNAs)may allow for disease“fingerprinting”and aid early central nervous system disease diagnosis,inform disease progression and response to therapy.This mini-review discusses recent advances in the field of peptidylarginine deiminase and extracellular vesicle research in the central nervous system,focusing on several central nervous system acute injury,degeneration and cancer models.

Cholinergic dysfunction-induced insufficient activation of alpha7 nicotinic acetylcholine receptor drives the development of rheumatoid arthritis through promoting protein citrullination via the SP3/PAD4 pathway

Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis(RA),but the relationship between the two phenomena remains unclear.We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA.Cholinergic function and protein citrullination levels in patients with RA and collageninduced arthritis(CIA)mice were collected.In both neuron-macrophage coculture system and CIA mice,the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases(PADs)was assessed by immunofluorescence.The key transcription factors for PAD4 expression were predicted and validated.Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues.The cholinergic or alpha7 nicotinic acetylcholine receptor(a7nAChR)deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo,respectively.Especially,the activation deficiency of a7nAChR induced the earlier onset and aggravation of CIA.Furthermore,deactivation of a7nAChR increased the expression of PAD4 and specificity protein-3(SP3)in vitro and in vivo.Our results suggest that cholinergic dysfunction-induced deficient a7nAChR activation,which induces the expression of SP3 and its downstream molecule PAD4,accelerating protein citrullination and the development of RA.

Tale of Two Alopecias: Alopecia Areata and Central Centrifugal Cicatricial Alopecia Occurring in the Same Patient

Introduction:Scarring and non-scarring alopecias have rarely been described to occur together in the same patient.Distinguishing these two different types of alopecia is important as treatment and prognosis can be different.Case presentation:Here,we report the first case of simultaneous alopecia areata(AA)and central centrifugal cicatricial alopecia(CCCA)in a 35-year-old woman.New alopecic patches were noted on her frontal and vertex scalp.Biopsy of the frontal scalp revealed miniaturized hair follicles and dense lymphocytic infiltrate surrounding the hair bulbs,consistent with AA;while biopsy of the vertex scalp revealed decreased hair follicles,perifollicular fibroplasia with eccentric atrophy of the follicular epithelium,and premature desquamation of the inner root sheath at the level of the lower isthmus,consistent with CCCA.Discussion:Proposed mechanisms of these two alopecia types occurring together include loss of immune privilege,genetic predisposition,as well as unknown external factors that trigger an autoimmune lymphocytic response.Most recently,the peptidylarginine deiminase type III gene has been implicated in both diseases.Although treatment options can overlap between thetwo diseases,treatment response can differ and CCCA tendsto have a worse prognosis.Conclusion:Awareness of this concomitant presentation of two alopecic types is important for appropriate treatment and prognostication.