Cross-talk between inflammation amd mitochondria in X-linked adrenoleukodystrophy (X-ALD) : an integrative approach towards diferent therapies

Parameswaran, Janani

Cross-talk between inflammation amd mitochondria in X-linked adrenoleukodystrophy (X-ALD) : an integrative approach towards diferent therapies

Document Type

Doctoral thesis
Published Version

Author

Parameswaran, Janani

Director

Pujol, Aurora

Publication Date

2018-03-09

Pages

125 p.

Citation

Parameswaran, J. Cross-talk between inflammation amd mitochondria in X-linked adrenoleukodystrophy (X-ALD) : an integrative approach towards diferent therapies. Universitat Pompeu Fabra; 2018. handle: http://hdl.handle.net/10803/664639

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Lack of function of ALDP in mouse leads to a late onset disease, characterized by spastic paraparesis and degeneration of corticospinal tracts, without signs of inflammatory demyelization resembling AMN patients. Taking advantage of this mice model and using primary glia cultures, we investigated the role of inflammation (mainly the pro and anti-inflammatory pattern) in X-ALD mice spinal cord and studied the contribution of microglia and astrocytes in disease pathogenesis. We found X-ALD mice spinal cord shows an inflammatory imbalance at 12 months of age. Similar observations were found in case of X-ALD mice primary microglia. In addition, we found mitochondria as the source of ROS in X-ALD mice microglia when insulted with C26:0. Activation of CB2 receptor prevents microgliosis and recovers all the altered parameters in X-ALD mice and thus halts axonal degeneration. Similar neuroprotective effects were observed with Methylene blue by targeting mitochondria.
La ausencia de función de ALDP en ratón conduce a una enfermedad tardía caracterizada por paraparesia espástica y degeneración del tracto corticoespinal sin signos de desmielinización inflamatoria, semejante a pacientes con AMN. Aprovechando este modelo y utilizando cultivos primarios de glía, hemos investigado el rol de la inflamación en la médula espinal del ratón X-ALD y la contribución de microglía y astrocitos en la patogénesis de la enfermedad. Hemos observado que la médula espinal muestra un desequilibrio inflamatorio a los 12 meses de edad. El mismo patrón se ha encontrado en cultivos primarios de microglía provenientes del mismo modelo, identificando además a la mitocondria como su fuente de ROS, tras tratarla con C26:0. Se han observado efectos neuroprotectores tales como la prevención de microgliosis y la recuperación de todos los parámetros alterados en los ratones los X-ALD, tanto activando los receptores CB2 como atacando dianas mitocondriales con azul de metileno.

Keywords

Reactive oxigen species, Microgliosis, Very long chain fatty acids, Methylene blue, Inflammation, Neurodegeneación, Endocannabinoides, Disfunción mitocondrial, Estrés oxidativo, Neuroprotector