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Neurochem Res. 2016 May;41(5):965-84. doi: 10.1007/s11064-015-1779-7. Epub 2015 Dec 8.

Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients Induces Mitochondrial and Lysosomal Dysfunction.

Author information

1
Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
2
Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
3
Institute of Bioinformatics, Discoverer Building, International Tech Park, Whitefield, Bangalore, 560066, India.
4
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
5
Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
6
Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India. bharath@nimhans.kar.nic.in.

Abstract

In our laboratory, we have developed (1) an in vitro model of sporadic Amyotrophic Lateral Sclerosis (sALS) involving exposure of motor neurons to cerebrospinal fluid (CSF) from sALS patients and (2) an in vivo model involving intrathecal injection of sALS-CSF into rat pups. In the current study, we observed that spinal cord extract from the in vivo sALS model displayed elevated reactive oxygen species (ROS) and mitochondrial dysfunction. Quantitative proteomic analysis of sub-cellular fractions from spinal cord of the in vivo sALS model revealed down-regulation of 35 mitochondrial proteins and 4 lysosomal proteins. Many of the down-regulated mitochondrial proteins contribute to alterations in respiratory chain complexes and organellar morphology. Down-regulated lysosomal proteins Hexosaminidase, Sialidase and Aryl sulfatase also displayed lowered enzyme activity, thus validating the mass spectrometry data. Proteomic analysis and validation by western blot indicated that sALS-CSF induced the over-expression of the pro-apoptotic mitochondrial protein BNIP3L. In the in vitro model, sALS-CSF induced neurotoxicity and elevated ROS, while it lowered the mitochondrial membrane potential in rat spinal cord mitochondria in the in vivo model. Ultra structural alterations were evident in mitochondria of cultured motor neurons exposed to ALS-CSF. These observations indicate the first line evidence that sALS-CSF mediated mitochondrial and lysosomal defects collectively contribute to the pathogenesis underlying sALS.

KEYWORDS:

Cerebrospinal fluid; Lysosome; Mitochondria; Motor neuron disease; Oxidative stress; Proteomics; Respiratory chain complexes

PMID:
26646005
DOI:
10.1007/s11064-015-1779-7
[Indexed for MEDLINE]

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