Characterising the role of cardiolpin in neurodegeneration
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Introduction
This PhD research project will be centred on the role of the mitochondrial phospholipid
cardiolipin in neurodegeneration, with a focus on frontotemporal dementia.
Background
Lipids play a crucial role in cellular metabolism and brain function. In the brain, lipids
account for approximately 50% of its dry weight, and they sustain the structure and
function of the CNS. Cardiolipin is a mitochondria-exclusive phospholipid that is mainly
localised within the inner mitochondrial membrane, which plays an essential role in the
architecture and function of mitochondria. Recently, aberrant cardiolipin content,
structure and localisation have been linked to impaired neurogenesis and neuronal
dysfunction, contributing to the pathogenesis of numerous neurodegenerative diseases,
for example Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD).
My research project will focus on understanding the role of cardiolipin metabolism in
mitochondrial function and nervous system homeostasis in cellular models of
frontotemporal dementia (FTD). FTD is a common form of young-onset dementia, which
is characterised by behavioural variants (bvFTD) and primary progressive aphasia (PPA),
with a gradual impairment of language skills. Genetic causes of FTD account for 20% to
50%, with the remaining cases being sporadic. However, understanding of the underlying
molecular mechanisms of FTD is incomplete.
A recent study published in February 2020 reported a decrease in CL levels and
mitochondrial dysfunction in FTD patients' serum. This is the first and only article that
suggests a potential link between CL and FTD, offering new opportunities to explore novel
mechanisms of the disease.
Methods
A wide range of laboratory techniques, including microscopy, cellular and molecular
biology, and mass spectroscopy, will be applied to interrogate the pathophysiological role
of aberrant CL content and mitochondrial dysfunction in FTD.
Neuroblastoma SH-SY5Y cells and FTD patient-derived cells will be used to investigate
cellular defects, focusing on CL and the state of the mitochondria. In addition, human
induced pluripotent stem cells (iPSCs) will be used to analyse molecular mechanisms in
neurons and microglia derived from FTD-patient fibroblasts.
Future perspectives
This research project aims to identify novel pathological mechanisms of FTD, while
assessing CL as a possible biomarker for neurodegeneration.
The potential discovery of CL as a novel biomarker to diagnose and monitor the
progression of neurodegenerative diseases would represent a valuable tool for diagnosis,
monitoring disease progression and measuring treatment effects in clinical trials.
Finally, the optimisation of the experiments will lay the foundations for future research
expanding the role of CL in other neurodegenerative diseases, such as amyotrophic lateral
sclerosis, AD and PD.
This PhD research project will be centred on the role of the mitochondrial phospholipid
cardiolipin in neurodegeneration, with a focus on frontotemporal dementia.
Background
Lipids play a crucial role in cellular metabolism and brain function. In the brain, lipids
account for approximately 50% of its dry weight, and they sustain the structure and
function of the CNS. Cardiolipin is a mitochondria-exclusive phospholipid that is mainly
localised within the inner mitochondrial membrane, which plays an essential role in the
architecture and function of mitochondria. Recently, aberrant cardiolipin content,
structure and localisation have been linked to impaired neurogenesis and neuronal
dysfunction, contributing to the pathogenesis of numerous neurodegenerative diseases,
for example Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD).
My research project will focus on understanding the role of cardiolipin metabolism in
mitochondrial function and nervous system homeostasis in cellular models of
frontotemporal dementia (FTD). FTD is a common form of young-onset dementia, which
is characterised by behavioural variants (bvFTD) and primary progressive aphasia (PPA),
with a gradual impairment of language skills. Genetic causes of FTD account for 20% to
50%, with the remaining cases being sporadic. However, understanding of the underlying
molecular mechanisms of FTD is incomplete.
A recent study published in February 2020 reported a decrease in CL levels and
mitochondrial dysfunction in FTD patients' serum. This is the first and only article that
suggests a potential link between CL and FTD, offering new opportunities to explore novel
mechanisms of the disease.
Methods
A wide range of laboratory techniques, including microscopy, cellular and molecular
biology, and mass spectroscopy, will be applied to interrogate the pathophysiological role
of aberrant CL content and mitochondrial dysfunction in FTD.
Neuroblastoma SH-SY5Y cells and FTD patient-derived cells will be used to investigate
cellular defects, focusing on CL and the state of the mitochondria. In addition, human
induced pluripotent stem cells (iPSCs) will be used to analyse molecular mechanisms in
neurons and microglia derived from FTD-patient fibroblasts.
Future perspectives
This research project aims to identify novel pathological mechanisms of FTD, while
assessing CL as a possible biomarker for neurodegeneration.
The potential discovery of CL as a novel biomarker to diagnose and monitor the
progression of neurodegenerative diseases would represent a valuable tool for diagnosis,
monitoring disease progression and measuring treatment effects in clinical trials.
Finally, the optimisation of the experiments will lay the foundations for future research
expanding the role of CL in other neurodegenerative diseases, such as amyotrophic lateral
sclerosis, AD and PD.