Phosphatidylinositol Monophosphates Regulate the Membrane Localization of HSPA1A, a Stress-Inducible 70-kDa Heat Shock Protein.

HSPA1A is a molecular chaperone that regulates the survival of stressed and cancer cells. In addition to its cytosolic pro-survival functions, HSPA1A also localizes and embeds in the plasma membrane (PM) of stressed and tumor cells. Membrane-associated HSPA1A exerts immunomodulatory functions and renders tumors resistant to standard therapies. Therefore, understanding and manipulating HSPA1A's surface presentation is a promising therapeutic. However, HSPA1A's pathway to the cell surface remains enigmatic because this protein lacks known membrane localization signals. Considering that HSPA1A binds to lipids, like phosphatidylserine (PS) and monophosphorylated phosphoinositides (PIPs), we hypothesized that this interaction regulates HSPA1A's PM localization and anchorage. To test this hypothesis, we subjected human cell lines to heat shock, depleted specific lipid targets, and quantified HSPA1A's PM localization using confocal microscopy and cell surface biotinylation. These experiments revealed that co-transfection of HSPA1A with lipid-biosensors masking PI(4)P and PI(3)P significantly reduced HSPA1A's heat-induced surface presentation. Next, we manipulated the cellular lipid content using ionomycin, phenyl arsine oxide (PAO), GSK-A1, and wortmannin. These experiments revealed that HSPA1A's PM localization was unaffected by ionomycin but was significantly reduced by PAO, GSK-A1, and wortmannin, corroborating the findings obtained by the co-transfection experiments. We verified these results by selectively depleting PI(4)P and PI(4,5)P2 using a rapamycin-induced phosphatase system. Our findings strongly support the notion that HSPA1A's surface presentation is a multifaceted lipid-driven phenomenon controlled by the binding of the chaperone to specific endosomal and PM lipids.

Rehabilitation of hand in subacute tetraplegic patients based on brain computer interface and functional electrical stimulation: a randomised pilot study.

OBJECTIVE: To compare neurological and functional outcomes between two groups of hospitalised patients with subacute tetraplegia. APPROACH: Seven patients received 20 sessions of brain computer interface (BCI) controlled functional electrical stimulation (FES) while five patients received the same number of sessions of passive FES for both hands. The neurological assessment measures were event related desynchronization (ERD) during movement attempt, Somatosensory evoked potential (SSEP) of the ulnar and median nerve; assessment of hand function involved the range of motion (ROM) of wrist and manual muscle test. MAIN RESULTS: Patients in both groups initially had intense ERD during movement attempt that was not restricted to the sensory-motor cortex. Following the treatment, ERD cortical activity restored towards the activity in able-bodied people in BCI-FES group only, remaining wide-spread in FES group. Likewise, SSEP returned in 3 patients in BCI-FES group, having no changes in FES group. The ROM of the wrist improved in both groups. Muscle strength significantly improved for both hands in BCI-FES group. For FES group, a significant improvement was noticed for right hand flexor muscles only. SIGNIFICANCE: Combined BCI-FES therapy results in better neurological recovery and better improvement of muscle strength than FES alone. For spinal cord injured patients, BCI-FES should be considered as a therapeutic tool rather than solely a long-term assistive device for the restoration of a lost function.

Hybrid brain-computer interface and functional electrical stimulation for sensorimotor training in participants with tetraplegia: a proof-of-concept study.

BACKGROUND AND PURPOSE: Impaired hand function decreases quality of life in persons with tetraplegia. We tested functional electrical stimulation (FES) controlled by a hybrid brain-computer interface (BCI) for improving hand function in participants with tetraplegia. METHODS: Two participants with subacute tetraplegia (participant 1: C5 Brown-Sequard syndrome, participant 2: complete C5 lesion) took part in this proof-of-concept study. The goal was to determine whether the BCI system could drive the FES device by accurately classifying participants' intent (open or close the hand). Participants 1 and 2 received 10 sessions and 4 sessions of BCI-FES, respectively. A novel time-switch BCI strategy based on motor imagery was used to activate the FES. In one session, we tested a hybrid BCI-FES based on 2 spontaneously generated brain rhythms: a sensory-motor rhythm during motor imagery to activate a stimulator and occipital alpha rhythms to deactivate the stimulator. Participants received BCI-FES therapy 2 to 3 times a week in addition to conventional therapy. Imagery ability and muscle strength were measured before and after treatment. RESULTS: Visual feedback was associated with a 4-fold increase of brain response during motor imagery in both participants. For participant 1, classification accuracy (open/closed) for motor imagery-based BCI was 83.5% (left hand) and 83.8% (right hand); participant 2 had a classification accuracy of 83.8% for the right hand. Participant 1 had moderate improvement in muscle strength, while there was no change for participant 2. DISCUSSION AND CONCLUSION: We demonstrated feasibility of BCI-FES, using 2 naturally generated brain rhythms. Studies on a larger number of participants are needed to separate the effects of BCI training from effects of conventional therapy.Video Abstract available. (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A84) for more insights from the authors.