Inflammation-induced PINCH expression leads to actin depolymerization and mitochondrial mislocalization in neurons.

BACKGROUND: Diseases and disorders with a chronic neuroinflammatory component are often linked with changes in brain metabolism. Among neurodegenerative disorders, people living with human immunodeficiency virus (HIV) and Alzheimer's disease (AD) are particularly vulnerable to metabolic disturbances, but the mechanistic connections of inflammation, neurodegeneration and bioenergetic deficits in the central nervous system (CNS) are poorly defined. The particularly interesting new cysteine histidine-rich-protein (PINCH) is nearly undetectable in healthy mature neurons, but is robustly expressed in tauopathy-associated neurodegenerative diseases including HIV infection and AD. Although robust PINCH expression has been reported in neurons in the brains of patients with HIV and AD, the molecular mechanisms and cellular consequences of increased PINCH expression in CNS disease remain largely unknown. METHODS: We investigated the regulatory mechanisms responsible for PINCH protein-mediated changes in bioenergetics, mitochondrial subcellular localization and bioenergetic deficits in neurons exposed to physiological levels of TNFα or the HIV protein Tat. Changes in the PINCH-ILK-Parvin (PIP) complex association with cofilin and TESK1 were assessed to identify factors responsible for actin depolymerization and mitochondrial mislocalization. Lentiviral and pharmacological inhibition experiments were conducted to confirm PINCH specificity and to reinstate proper protein-protein complex communication. RESULTS: We identified MEF2A as the PINCH transcription factor in neuroinflammation and determined the biological consequences of increased PINCH in neurons. TNFα-mediated activation of MEF2A via increased cellular calcium induced PINCH, leading to disruption of the PIP ternary complex, cofilin activation by TESK1 inactivation, and actin depolymerization. The disruption of actin led to perinuclear mislocalization of mitochondria by destabilizing the kinesin-dependent mitochondrial transport machinery, resulting in impaired neuronal metabolism. Blocking TNFα-induced PINCH expression preserved mitochondrial localization and maintained metabolic functioning. CONCLUSIONS: This study reported for the first time the mechanistic and biological consequences of PINCH expression in CNS neurons in diseases with a chronic neuroinflammation component. Our findings point to the maintenance of PINCH at normal physiological levels as a potential new therapeutic target for neurodegenerative diseases with impaired metabolisms.

The Effects of Spinal Cord Stimulators on End Organ Perfusion: A Literature Review.

Spinal cord stimulators (SCS) have been gaining momentum in the last decade as their role in the management of chronic pain has become more apparent. Our intention was to search, analyze and highlight the effects of spinal cord stimulators on end-organ perfusion. We also looked at vascular diseases of atherosclerotic and nonatherosclerotic nature by examining objective evidence of improved circulation, pain control, limb salvage, and quality of life. We paid specific attention to disease processes such as cerebral hypoperfusion, Chronic-Critical Limb Ischemia, Intractable Angina Pectoris (IAP), Raynaud's syndrome and Thromboangiitis Obliterans. We performed a Medline database search for medical literature relevant to Spinal cord stimulators encompassing the years 1950 to 2019. Search terms included "Spinal cord stimulator," plus one of the following search terms: vasculopathy, stroke, cerebral blood flow, angina pectoris, diabetic ulcers, chronic critical leg ischemia, thromboangiitis obliterans and peripheral vascular disease. We included both clinical and experimental human studies that investigated the effect of SCS's on end-organ perfusion. We also investigated the pathophysiological mechanism of action of SCS's on the vasculature. We found 497 articles of which 43 more relevant and impactful articles investigating the hemodynamic effects of SCS and its possible mechanism were selected. Animal studies were excluded from the literature review as they provided heterogeneity. In addition to reporting literature supporting the use of stimulators for currently FDA approved uses, we also actively looked for potential future uses. Spinal Cord stimulators showed improvement in cerebral blood flow, increased capillary recruitment, and better quality of life in many studies. Patients also had increased exercise capacity and a significant reduction in the use of narcotic drug use and daily anginal attacks in patients suffering from IAP.

Neurosyphilis Presenting as Intermittent Explosive Disorder and Acute Psychosis.

We present a case of a patient with tertiary syphilis, manifesting as acute psychosis, auditory hallucinations and intermittent explosive disorder with pending legal ramifications for physical violence. Our patient had been seen and treated by a psychologist with Aripiprazole for his erratic and aggressive behavior coupled with his new found psychosis over a one-year period with no avail. Prior accounts of interaction with the patient described him as "easy going", "laid back", and cooperative. Our patient had a complete return to baseline mentation and functionality post treatment with 4 Million Units every four hours of penicillin for two weeks. Neurosyphilis is a disease that greatly affects the mental functioning capacity of those infected. While treatment of syphilis has become greatly straightforward, those living in impoverished conditions and without a continual access to the health care system can progress through the stages of syphilis. It is of vital importance to keep syphilis on our differential for patients with rapidly progressing and broadly encompassing psychiatric disturbances especially in patients that have a lower socioeconomic status.

Cocaine and HIV-1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV-associated neurocognitive disorders in cocaine user patients.

Cholesterol synthesis and clearance by astrocytes are tightly regulated to maintain constant levels within the brain. In this context, liver X receptors (LXRs) are the master regulators of cholesterol homeostasis in the central nervous system (CNS). Increasing levels of cholesterol in astrocytes trigger LXR activation leading to the transcription of target genes involved in cholesterol trafficking and efflux, including apolipoprotein E, cytochrome P450 enzymes, sterol regulatory binding protein, and several ATP-binding cassette transporter proteins. The disturbance of LXR signaling in the brain can lead to significant dysfunctions in cholesterol homeostasis, and disruptions in this pathway have been implicated in numerous neurological diseases including Alzheimer's disease and Huntington's disease. HIV infection of the CNS in combination with cocaine use is associated with astrocyte and neuronal energy deficit and damage. We propose that dysregulation in CNS cholesterol metabolism may be involved in the progression of HIV-associated neurocognitive disorders (HAND) and in cocaine-mediated neurocognitive impairments. We hypothesize that exposure of astrocytes to cocaine and the HIV protein Tat will disrupt LXR signaling. Alterations in these pathways will in turn, affect cholesterol bioavailability for neurons. Our data show that exposure of astrocytes to cocaine and HIV-Tat significantly decreases LXRß levels, downstream signaling and bioavailability of cholesterol. Taken together, these data uncover novel alterations in a bioenergetic pathway in astrocytes exposed to cocaine and the HIV protein Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine user individuals.