Inflammation induced-PINCH expression leads to actin depolymerization and mitochondrial mislocalization in neurons release_fv7yvghb65gp7begg2syblbbqq

by Dianne Langford, Kalimuthusamy Natarajaseenivasan, Santhanam Shanmughapriya, Prema Velusamy, Matthew Sayre, Alvaro Garcia, Nestor Mas Gomez

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<title>Abstract</title> 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 mechanistic connections of inflammation, neurodegeneration and bioenergetic deficits in the central nervous system (CNS) are poorly defined. The particularly interesting new cystine histidine-rich protein called 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 was not known. In this context, we have identified the transcription factor responsible for PINCH induction in neuroinflammatory conditions and the effects of increased PINCH expression in neurons. Given that AD and neuroHIV share pathological features including cognitive impairment with chronic neuroinflammation, TNFa plays an important role in neurodegenerative processes. The viral protein Tat, is produced in the brain and is one of the main drivers of neuroinflammation and strongly induces TNFa. Our data show that TNFα-mediated activation of MEF2A via increased cellular calcium induces PINCH. In turn, this leads to disruption of the PINCH-ILK-Parvin ternary complex, cofilin activation by Tesk1 inactivation, and actin depolymerization. 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 preserves mitochondrial localization and maintains metabolic functioning. These data report for the first time mechanistic and biological consequences of PINCH expression in neurons in the CNS in diseases with a chronic neuroinflammatory component. These findings point to maintenance of PINCH at normal physiological levels as a new therapeutic target for neurodegenerative diseases with impaired metabolism.
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