Cerebrospinal fluid from sporadic amyotrophic lateral sclerosis patients induces mitochondrial and lysosomal dysfunction

International Congress on Neuroimmunology and Therapeutics

DoubleTree by Hilton Hotel San Francisco Airport, San Francisco, CA, USA

Aparna Sharma

Posters-Accepted Abstracts: J Neurol Disord

Abstract :

Background: Mitochondrial dysfunction is amongst the pivotal mechanisms in the Amyotrophic Lateral Sclerosis (ALS) pathogenesis. It is an early pathological feature in the familial mutant SOD1 transgenic mice, preceding the onset of motor weakness and is also seen in sporadic ALS. Purpose: To study the mitochondrial damage induced by CSF of ALS patients (ALS-CSF) in Wistar rats. Introduction: Sporadic pathology accounts for >90% of the cases of amyotrophic lateral sclerosis (ALS). We had previously developed an in vivo model of the disease involving intrathecal injection of cerebrospinal fluid (CSF) from sporadic ALS patients into rat pups. Compared to normal-CSF (N-CSF) and untreated control, ALS-CSF induced markers of neurodegeneration in motor neurons. In cultured motor neurons, ALS-CSF induced neurotoxicity, lowered mitochondrial membrane potential and elevated reactive oxygen species (ROS). Quantitative proteomic analysis of sub-cellular fractions from spinal cord of rats injected with ALS-CSF revealed down-regulation of 37 mitochondrial proteins and 4 lysosomal proteins. Many of the down-regulated proteins contribute to respiratory chain complexes and mitochondrial morphology. The lysosomal proteins down-regulated in the model showed lowered enzyme activity, thus validating the mass spectrometry data. Proteomic analysis validated by western blot indicated that ALS-CSF induced the over-expression of the apoptotic protein BNIP3. Ultrastructural alterations were evident in mitochondria of cultured motor neurons exposed to ALS-CSF. These observations indicate that ALS-CSF mediated mitochondrial and lysosomal defects could contribute to the pathogenesis underlying sporadic ALS.