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

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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.

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Abbreviations

fALS:

Familial Amyotrophic Lateral Sclerosis

sALS:

Sporadic Amyotrophic Lateral Sclerosis

CSF:

Cerebrospinal fluid

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

iTRAQ:

Isobaric tag for relative and absolute quantitation

CI:

Mitochondrial complex I

CII:

Mitochondrial complex II

CIII:

Mitochondrial complex III

CIV:

Mitochondrial complex IV

CV:

Mitochondrial complex V

LC–MS/MS:

Liquid chromatography–tandem mass spectrometry

HEX:

Hexosaminidase

ARS:

Arylsulphatase

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Acknowledgments

This study was funded by funded by the Department of Biotechnology (DBT), Govt. of India (BT/PR/4054/Med/30/349/2010). The authors thank the all the patients for permitting to utilize the CSF samples for this study. The authors are grateful to the Director, Sanjay Gandhi Institute of Trauma and Orthopedics Centre, Bangalore, for facilitating the collection of control CSF. A.M.V., S.S. and K.K.D. are senior research fellows of the Council of Scientific and Industrial Research (CSIR), India. R.R.S. is a senior research fellow of the Indian Council of Medical Research (ICMR). H.G. is supported by an early career fellowship from Welcome Trust-DBT India Alliance.

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  1. Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India

    Aparna Sharma, Anu Mary Varghese, Kalyan Vijaylakshmi, Rajendrarao Sumitha, V. K. Prasanna, S. Shruthi, Phalguni Anand Alladi, Talakad N. Sathyaprabha & Trichur R. Raju

  2. Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India

    Rita Christopher & M. M. Srinivas Bharath

  3. Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India

    B. K. Chandrasekhar Sagar

  4. Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India

    Atchayaram Nalini

  5. Institute of Bioinformatics, Discoverer Building, International Tech Park, Whitefield, Bangalore, 560066, India

    Keshava K. Datta & Harsha Gowda

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Sharma, A., Varghese, A.M., Vijaylakshmi, K. et al. Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients Induces Mitochondrial and Lysosomal Dysfunction. Neurochem Res 41, 965–984 (2016). https://doi.org/10.1007/s11064-015-1779-7

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  • DOI: https://doi.org/10.1007/s11064-015-1779-7

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