Transmembrane protease serine 5: a novel Schwann cell plasma marker for CMT1A

Abstract

ObjectiveDevelopment of biomarkers for Charcot‐Marie‐Tooth (CMT) disease is critical for implementing effective clinical trials. The most common form of CMT, type 1A, is caused by a genomic duplication surrounding the PMP22 gene. A recent report (Neurology 2018;90:e518–3524) showed elevation of neurofilament light (NfL) in plasma of CMT1A disease patients, which correlated with disease severity. However, no plasma/serum biomarker has been identified that is specific to Schwann cells, the most directly affected cells in CMT1A.MethodsWe used the Olink immuno PCR platform to profile CMT1A patient (n = 47, 2 cohorts) and normal control plasma (n = 41, two cohorts) on five different Olink panels to screen 398 unique proteins.ResultsThe TMPRSS5 protein (Transmembrane protease serine 5) was elevated 2.07‐fold (P = <0.0001) in two independent cohorts of CMT1A samples relative to controls. TMPRSS5 is most highly expressed in Schwann cells of peripheral nerve. Consistent with early myelination deficits in CMT1A, TMPRSS5 was not significantly correlated with disease score (CMTES‐R, CMTNS‐R), nerve conduction velocities (Ulnar CMAP, Ulnar MNCV), or with age. TMPRSS5 was not significantly elevated in smaller sample sets from patients with CMT2A, CMT2E, CMT1B, or CMT1X. The Olink immuno PCR assays confirmed elevated levels of NfL (average 1.58‐fold, P < 0.0001), which correlated with CMT1A patient disease score.InterpretationThese data identify the first Schwann cell‐specific protein that is elevated in plasma of CMT1A patients, and may provide a disease marker and a potentially treatment‐responsive biomarker with good disease specificity for clinical trials.

Metabolic and muscle-derived serum biomarkers define CHCHD10-linked late-onset spinal muscular atrophy

“…The axonal injury protein NfL has shown to be a potent serum biomarker in a number of neurological conditions (17), including ALS, CMT and SMA (18,19,20). However, in our measurements, the level of serum NfL was not significantly different in SMAJ patient samples (median 14.9 pg/ml) compared to controls (13.6 pg/ml) (Fig 1A).…”

Identification of Candidate Genes Associated with Charcot-Marie-Tooth Disease by Network and Pathway Analysis

“…The correlative module could be grouped into five modules: the first module was mainly dominated by the biological processes related to the activity of the nervous system. Among these biological processes, axon ensheathment, myelination, peripheral nervous system development, and Schwann cell development have been well studied, involving the axons, myelin sheaths, or peripheral nervous system as well as the progress of Charcot-Marie-Tooth Disease [ 46 – 49 ]. The second module and the third module can be defined together as a transmission function-related biological process.…”

Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: the past, the present and the future

“…56 Another biomarker found to be elevated in CMT1A plasma sample is the neurofilament L protein that was correlated with the increase in the severity of CMTN scores in CMT1A patient. 57 A new specific biomarker for CMT1A was recently identified by Wang et al 58 The transmembrane protease serine 5 (TMPRSS5) protein was found to be elevated by around 2-folds in the plasma of CMT1A patients. 58 Moreover, several genes were found to be alteredin PMP22 transgenic mouse model (TgN248) that could be targeted for future therapy.…”

“…57 A new specific biomarker for CMT1A was recently identified by Wang et al 58 The transmembrane protease serine 5 (TMPRSS5) protein was found to be elevated by around 2-folds in the plasma of CMT1A patients. 58 Moreover, several genes were found to be alteredin PMP22 transgenic mouse model (TgN248) that could be targeted for future therapy. 59 Since the discovery of the main cause of CMT1A, that is PMP22 overexpression resulting from the trisomy of PMP22 gene in addition to neurological dysfunctions which are due to loss of large-caliber motor and sensory axons, several animal models and therapeutic strategies were developed.…”