Midtveisevaluering- Kristin Nielsen Varhaug

Kristin Nielsen Varhaug er tilknyttet Klinisk institutt 1. Veiledere er Laurence Albert Bindoff og Christian Vedeler.

PhD project

Biomarkers of mitochondrial dysfunction and neurodegeneration

By Kristin Nielsen Varhaug

Abstract

Introduction

A biomarker is defined as objective indications of medical condition that can be measured accurately and reproducibly. Neurodegeneration defines the process were neurons loose structure or function, culminating in neuronal death. Mitochondrial dysfunction is increasingly recognized as a central feature of neurodegeneration.

The aim of this thesis is to understand more of the mitochondrial role in neurodegenerative disorders, and, in turn, use this knowledge to identify novel biomarkers and diagnostic approaches for diseases.   

Methods

The material includes 1. CSF and serum from patients with multiple sclerosis (MS). 2. muscle and urine samples from patients with primary mitochondrial disease, and 3. a mouse model of demyelination (the cuprizone-model).

A range of laboratory techniques have been utilized. Mitochondrial DNA (mtDNA) has been identified by the use of quantitative polymerase-chain reaction (qPCR), long-range PCR, standard PCR and sequencing analysis. Neurofilament light chain (NF-L) has been identified using enzyme-linked immunosorbent assay (ELISA). Assessment of quantitative and qualitative properties of the respiratory chain in the mouse model have been done with immunohistochemistry.

Results

In MS patients NF-L levels and cell-free mtDNA levels are elevated, and reflect disease activity and treatment response (NF-L). In the mouse model complex IV of the respiratory chain in neurons seem affected by cuprizone.

Conclusion

Elevated NF-L and mtDNA levels in MS patients suggest both are potential biomarkers for the disease, and also underline the neurodegenerative component in MS. Although the Cuprizone-model is not an ideal “MS-model” it reflects aspects of demyelination, and also here mitochondria dysfunction is found, showing subtle changes of neurodegenerative processes in what is otherwise known as normal-appearing neurons.