Patient-Reported Symptom Burden of Charcot-Marie-Tooth Disease Type 1A: Findings From an Observational Digital Lifestyle Study.

OBJECTIVES: This study aims to explore the impact of Charcot-Marie-Tooth disease type 1A (CMT1A) and its treatment on patients in European (France, Germany, Italy, Spain, and the United Kingdom) and US real-world practice. METHODS: Adults with CMT1A (n = 937) were recruited to an ongoing observational study exploring the impact of CMT. Data were collected via CMT&Me, an app through which participants completed patient-reported outcome measures. RESULTS: Symptoms ranked with highest importance were weakness in the extremities, difficulty in walking, and fatigue. Almost half of participants experienced a worsening of symptom severity since diagnosis. Anxiety and depression were each reported by over one-third of participants. Use of rehabilitative interventions, medications, and orthotics/walking aids was high. CONCLUSIONS: Patient-reported burden of CMT1A is high, influenced by difficulties in using limbs, fatigue, pain, and impaired quality of life. Burden severity appears to differ across the population, possibly driven by differences in rehabilitative and prescription-based interventions, and country-specific health care variability.

Programmed cell death protein 5 interacts with the cytosolic chaperonin containing tailless complex polypeptide 1 (CCT) to regulate ß-tubulin folding.

Programmed cell death protein 5 (PDCD5) has been proposed to act as a pro-apoptotic factor and tumor suppressor. However, the mechanisms underlying its apoptotic function are largely unknown. A proteomics search for binding partners of phosducin-like protein, a co-chaperone for the cytosolic chaperonin containing tailless complex polypeptide 1 (CCT), revealed a robust interaction between PDCD5 and CCT. PDCD5 formed a complex with CCT and ß-tubulin, a key CCT-folding substrate, and specifically inhibited ß-tubulin folding. Cryo-electron microscopy studies of the PDCD5·CCT complex suggested a possible mechanism of inhibition of ß-tubulin folding. PDCD5 bound the apical domain of the CCTß subunit, projecting above the folding cavity without entering it. Like PDCD5, ß-tubulin also interacts with the CCTß apical domain, but a second site is found at the sensor loop deep within the folding cavity. These orientations of PDCD5 and ß-tubulin suggest that PDCD5 sterically interferes with ß-tubulin binding to the CCTß apical domain and inhibits ß-tubulin folding. Given the importance of tubulins in cell division and proliferation, PDCD5 might exert its apoptotic function at least in part through inhibition of ß-tubulin folding.

Role of molecular chaperones in G protein beta5/regulator of G protein signaling dimer assembly and G protein betagamma dimer specificity.

The G protein betagamma subunit dimer (Gbetagamma) and the Gbeta5/regulator of G protein signaling (RGS) dimer play fundamental roles in propagating and regulating G protein pathways, respectively. How these complexes form dimers when the individual subunits are unstable is a question that has remained unaddressed for many years. In the case of Gbetagamma, recent studies have shown that phosducin-like protein 1 (PhLP1) works as a co-chaperone with the cytosolic chaperonin complex (CCT) to fold Gbeta and mediate its interaction with Ggamma. However, it is not known what fraction of the many Gbetagamma combinations is assembled this way or whether chaperones influence the specificity of Gbetagamma dimer formation. Moreover, the mechanism of Gbeta5-RGS assembly has yet to be assessed experimentally. The current study was undertaken to directly address these issues. The data show that PhLP1 plays a vital role in the assembly of Ggamma2 with all four Gbeta1-4 subunits and in the assembly of Gbeta2 with all twelve Ggamma subunits, without affecting the specificity of the Gbetagamma interactions. The results also show that Gbeta5-RGS7 assembly is dependent on CCT and PhLP1, but the apparent mechanism is different from that of Gbetagamma. PhLP1 seems to stabilize the interaction of Gbeta5 with CCT until Gbeta5 is folded, after which it is released to allow Gbeta5 to interact with RGS7. These findings point to a general role for PhLP1 in the assembly of all Gbetagamma combinations and suggest a CCT-dependent mechanism for Gbeta5-RGS7 assembly that utilizes the co-chaperone activity of PhLP1 in a unique way.