Professor Heather Mortiboys
PhD
Neuroscience, School of Medicine and Population Health
Head of Neuroscience
Professor of Cellular Neuroscience and Metabolism
h.mortiboys@sheffield.ac.uk
+44 114 222 2259
+44 114 222 2259
+44 114 222 2261
(Administrator: Rebecca Brown)
Room B50, Sheffield Institute for Translational Neuroscience (SITraN)
Full contact details
Professor Heather Mortiboys
Neuroscience, School of Medicine and Population Health
Room B50
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ
Neuroscience, School of Medicine and Population Health
Room B50
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ
- Profile
-
I was awarded my PhD from the International Max Planck PhD Program in Dresden Germany in 2006 with the grade summa cum laude; this project focused on the ‘Influence of mitochondrial energy metabolism on cellular function: implications for neurometabolic and neurodegenerative diseases.’
After which I worked in the Neurology department at the University Hospital Dresden as a research associate on an EU funded project investigating Co-enzyme Q deficiency in patient tissue.
I joined the Neuroscience department at the University of Sheffield in 2006 to set up mitochondrial investigations in models of Parkinson’s Disease working as a postdoctoral research associate with Prof. Oliver Bandmann.
I started my own lab when I became a Parkinson’s UK Senior Research Fellow in September 2013 based within the Sheffield Institute for Translational Neuroscience (SITraN).
- Research interests
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The main focus of my lab is mitochondria in neurodegenerative diseases, primarily focused on Parkinson’s Disease. This encompasses mitochondrial function, DNA, morphology and recycling as well as links with other cellular pathways.
My research focuses on both trying to further the understanding of the causes of mitochondrial problems in neurodegenerative conditions and in vitro drug screening for molecules which rescue mitochondrial function in patient tissue.
The lab has also recently become interested in investigating these mitochondrial abnormalities in Alzheimer’s Disease and Motor Neuron Disease patient derived cells. It is interesting to investigate the differing mitochondrial phenotypes between neurodegenerative diseases and the mechanisms by which they occur and potentially drive neuronal vulnerability.
Current projects
- Targeting mitochondrial dysfunction with novel small molecules in Parkinson’s Disease and Alzheimer’s Disease
- Repurposing of compounds for the treatment of Parkinson’s Disease
- LRRK2 and mitochondria – what is the connection?
- Differing types of mitophagy in neurons and astrocytes
- Targeting mitophagy with small molecules in Parkinson’s Disease
- Mitochondrial morphological abnormalities in patient derived models of Alzheimer’s Disease
- What are the metabolic abnormalities in Motor Neuron Disease
- Publications
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Journal articles
- Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes inC9orf72ALS/FTD models. Life Science Alliance, 7(9), e202402853-e202402853.
- The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress. Biochemical Journal, 481(4), 265-278.
- Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis. Heliyon, 10(3), e24975-e24975.
- Deficits in mitochondrial function and glucose metabolism seen in sporadic and familial Alzheimer’s disease derived Astrocytes are ameliorated by increasing hexokinase 1. Alzheimer's & Dementia, 19(S13).
- Multimodal assessment of mitochondrial function in Parkinson's disease. Brain, awad364.
- Clinical Trial Highlights: Modulators of Mitochondrial Function. Journal of Parkinson's Disease, 13(6), 851-864.
- Outcome Measures for Disease-Modifying Trials in Parkinson’s Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative. Journal of Parkinson's Disease, 13(6), 1011-1033.
- Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency. Disease Models & Mechanisms, 16(6).
- FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels. The EMBO Journal.
- A p21‐GFP zebrafish model of senescence for rapid testing of senolytics in vivo. Aging Cell.
- Using 31-phosphorus magnetic resonance spectroscopy (31P-MRS) to identify Parkinson’s Disease subgroups with bioenergetic dysfunction. Journal of Neurology, Neurosurgery & Psychiatry, 93(9), e2.2-e2.2.
- Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy. Life Science Alliance, 5(2).
- Brain energy metabolism in ALS: A phosphorus-31 magnetic resonance spectroscopy study. Journal of the Neurological Sciences, 429, 119412.
- The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity. Molecular Psychiatry. View this article in WRRO
- A Parkinson’s disease-relevant mitochondrial and neuronal morphology high-throughput screening assay in LUHMES cells. Bio-protocol, 11(1).
- Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease. Aging Cell. View this article in WRRO
- Do deficits in mitochondrial spare respiratory capacity contribute to neuropsychological changes seen in Alzheimer’s disease?. Alzheimer's & Dementia, 16(S6).
- Peripheral glycolysis in neurodegenerative diseases. International Journal of Molecular Sciences, 21(23).
- Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons. Scientific Reports, 10(1).
- USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylation. Life Science Alliance, 3(8). View this article in WRRO
- Deficits in mitochondrial spare respiratory capacity contribute to the neuropsychological changes of alzheimer’s disease. Journal of Personalized Medicine, 10(2). View this article in WRRO
- Do deficits in Mitochondrial Spare Respiratory Capacity contribute to Neuropsychological changes seen in Alzheimer’s disease? (798). Neurology, 94(15_supplement).
- Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson’s disease. Progress in Neurobiology, 187.
- C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis. Brain, 1-20. View this article in WRRO
- TIGAR inclusion pathology is specific for Lewy body diseases. Brain Research, 1706, 218-223. View this article in WRRO
- Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with either Sporadic or Familial Alzheimer's Disease. Journal of Molecular Biology, 430(21), 3942-3953. View this article in WRRO
- Loss of IGF1R in human astrocytes alters complex I activity and support for neurons.. Neuroscience, 390, 46-59. View this article in WRRO
- Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?. Biochemical Society Transactions, 46(4), 891-909. View this article in WRRO
- Translational approaches to restoring mitochondrial function in Parkinson's disease. FEBS Letters, 592(5), 776-792. View this article in WRRO
- PO076 Disease stratification in sporadic parkinson’s disease. Journal of Neurology, Neurosurgery & Psychiatry, 88(Suppl 1), A31.4-A32.
- [P4-034]: MITOCHONDRIAL ABNORMALITIES ARE FOUND IN FIBROBLASTS FROM SPORADIC ALZHEIMER's DISEASE PATIENTS: RECOVERY WITH URSODOXYCHOLIC ACID TREATMENT. Alzheimer's & Dementia, 13(7S_Part_26), P1269-P1269.
- Modulating mitophagy in mitochondrial disease.. Curr Med Chem. View this article in WRRO
- Inhibition of the mitochondrial calcium uniporter (MCU) rescues dopaminergic neurons in pink1-/- zebrafish. European Journal of Neuroscience, 45(4), 528-535. View this article in WRRO
- Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations. Neurology, 88(2), 131-142. View this article in WRRO
- Screening for chemical modulators for LRRK2.. Biochemical Society Transactions, 44(6), 1617-1623. View this article in WRRO
- Rescue of mitochondrial function in parkin-mutant Fibroblasts using drug loaded PMPC-PDPA polymersomes and tubular polymersomes. Neuroscience Letters, 630, 23-29. View this article in WRRO
- Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death. Human Molecular Genetics, 24(23), 6640-6652. View this article in WRRO
- A novel quantitative assay of mitophagy: Combining high content fluorescence microscopy and mitochondrial DNA load to quantify mitophagy and identify novel pharmacological tools against pathogenic heteroplasmic mtDNA. Pharmacological Research, 100, 24-35.
- UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2G2019S carriers and in vivo. Neurology, 85(10), 846-852.
- The Complex I Subunit NDUFA10 Selectively Rescues Drosophila pink1 Mutants through a Mechanism Independent of Mitophagy. PLoS Genetics, 10(11). View this article in WRRO
- IHG-1 increases mitochondrial fusion and bioenergetic function.. Diabetes, 63(12), 4314-4325.
- TIGAR Inhibition Rescues Dopaminergic Neurons in Common Forms of Early Onset Parkinson's' Disease (S7.002). Neurology, 82(10_supplement).
- TIGAR Inhibition Rescues Dopaminergic Neurons in Common Forms of Early Onset Parkinson's' Disease (I5-2.003). Neurology, 82(10_supplement).
- P33 Do modulators of mitophagy select pathogenic mtDNA mutations?. Neuromuscular Disorders, 24, S15-S15.
- Superoxide dismutase 1 mutation in a cellular model of amyotrophic lateral sclerosis shifts energy generation from oxidative phosphorylation to glycolysis.. Neurobiol Aging, 35(6), 1499-1509.
- Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson's disease.. Brain, 136(Pt 10), 3038-3050.
- TigarB causes mitochondrial dysfunction and neuronal loss in PINK1 deficiency.. Ann Neurol, 74(6), 837-847. View this article in WRRO
- The Effect of SOD1 Mutation on Cellular Bioenergetic Profile and Viability in Response to Oxidative Stress and Influence of Mutation-Type.. Plos One, 6(8), e68256-e68256. View this article in WRRO
- Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2.. Neurology, 75(22), 2017-2020.
- POMD08 Zebrafish models for early onset Parkinson's disease.. J Neurol Neurosurg Psychiatry, 81(11), e59.
- A PINK1 Mutant Zebrafish Model of Early Onset Parkinson's Disease. MOVEMENT DISORD, 25, S631-S631.
- Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS).. PLoS One, 5(3), e9872. View this article in WRRO
- Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss.. Nature Neuroscience, 12(9), 1129-1135. View this article in WRRO
- Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio).. Brain, 132(Pt 6), 1613-1623.
- 7. Mitochondrial function and morphology are impaired in parkin mutant fibroblasts. Mitochondrion, 9(1), 63-63.
- Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts.. Ann Neurol, 64(5), 555-565.
- Light affects mitochondria to cause apoptosis to cultured cells: possible relevance to ganglion cell death in certain optic neuropathies.. J Neurochem, 105(5), 2013-2028.
- Mitochondrial dysfunction in Parkinson's disease--revisited.. Neurol Neurochir Pol, 41(2), 150-159.
- Primärer Coenzym Q10-Mangel bei einem Erwachsenen. Aktuelle Neurologie, 33(S 1).
- Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer’s disease astrocytes. Molecular Psychiatry.
- Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease. Nature Communications.
- Correction to “A
p21‐GFP zebrafish model of senescence for rapid testing of senolytics in vivo”. Aging Cell.
- The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function. Nature Communications, 14(1).
- Aging, Parkinson’s Disease, and Models: What Are the Challenges?. Aging Biology, 1(1), 20230010-20230010.
- Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinson’s disease. Brain.
- 3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease. Biomolecules, 13(1), 76-76.
- Direct Reprogramming Retains Aging Signatures That Are Critical to Reveal Parkinson's Disease-Associated Autophagy Phenotypes. Cellular Reprogramming.
- Persistent DNA damage alters the neuronal transcriptome suggesting cell cycle dysregulation and altered mitochondrial function. European Journal of Neuroscience.
- Defekte der mitochondrialen Atmungskette bei idiopathischem Parkinson-Syndrom. Aktuelle Neurologie, 32(S 4).
- The common PARK8 mutation LRRK2 G2019S is not a risk factor for breast cancer in the absence of Parkinson's disease.. Journal of Neurology.
- Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis. Brain.
- Mitochondrial Dysfunction in Alzheimer’s Disease: A Biomarker of the Future?. Biomedicines, 9(1), 63-63.
Chapters
- Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems, International Review of Neurobiology Elsevier
Conference proceedings papers
- I026 Screening for mitochondrial therapeutics in Huntington’s disease using patient-derived cells. I: Experimental therapeutics – preclinical (pp A152.1-A152)
- Treatment Selection in Multi-Arm Multi-Stage Clinical Trials in Parkinson Disease: The Search for the Ideal Neuroprotective Drug. MOVEMENT DISORDERS, Vol. 37 (pp S329-S329)
- Multimodal mechanistic disease stratification in sporadic Parkinson's disease. MOVEMENT DISORDERS, Vol. 37 (pp S113-S113)
- Developing 31-phosphorus magnetic resonance spectroscopy (31P-MRS) as an imaging biomarker to identify mitochondrial dysfunction in Parkinson's disease. MOVEMENT DISORDERS, Vol. 36 (pp S370-S371)
- (31)Phosphorus Magnetic Resonance Spectroscopy as a Tool to Identify Mitochondrial Dysfunction in Parkinson's Disease In-Vivo. ANNALS OF NEUROLOGY, Vol. 90 (pp S152-S153)
- Do deficits in Mitochondrial Spare Respiratory Capacity contribute to Neuropsychological changes seen in Alzheimer's disease?. NEUROLOGY, Vol. 94(15) View this article in WRRO
- Acid sphingomyelinase deficiency rescues mitochondrial dysfunction in gba-/- zebrafish (Danio rerio). MOVEMENT DISORDERS, Vol. 33 (pp S615-S615)
- Inhibition of the mitochondrial calcium uniporter (MCU) rescues dopaminergic neurons in pink1-/- zebrafish. MOVEMENT DISORDERS, Vol. 31 (pp S209-S209)
- Identifying novel pharmacological drugs to eliminate pathogenic heteroplasmic mtDNA by using a novel quantitative assay of mitophagy. NEUROMUSCULAR DISORDERS, Vol. 26 (pp S21-S21)
- Dysregulated mitophagy and mitochondrial transport in sensori-motor neuropathy due to “Dominant Optic Atrophy” plus with OPA1 (Optic Atrophy 1) mutations. Neuromuscular Disorders, Vol. 25 (pp S185-S186)
- Mitochondrial Impairment in Manifesting LRRK2-G2019S Carriers. NEUROLOGY, Vol. 74(9) (pp A255-A255)
- Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). MOVEMENT DISORDERS, Vol. 24 (pp S135-S135)
- Abnormal mitochondrial function and morphology in fibroblasts of patients with early onset Parkinson's disease and two parkin mutations. NEUROLOGY, Vol. 70(11) (pp A485-A485)
- Mitochondrial function and morphology in parkin mutant fibroblasts. MOVEMENT DISORDERS, Vol. 23(1) (pp S49-S49)
Datasets
Preprints
- The Parkinson's Disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress, Cold Spring Harbor Laboratory.
- Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction inC9orf72ALS/FTDin vivomodels and patient iNeurons, Cold Spring Harbor Laboratory.
- Deficits in mitochondrial function and glucose metabolism seen in sporadic and familial Alzheimer’s disease derived Astrocytes are ameliorated by increasing hexokinase 1 expression, Cold Spring Harbor Laboratory.
- Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease, Research Square Platform LLC.
- FBXL4 deficiency promotes mitophagy by elevating NIX, Cold Spring Harbor Laboratory.
- A p21-GFP zebrafish model of senescence for rapid testing of senolytics in vivo., Cold Spring Harbor Laboratory.
- TRANSCRIPTOMIC SIGNATURES OF TELOMERASE-DEPENDENT AND -INDEPENDENT AGEING, IN THE ZEBRAFISH GUT AND BRAIN, Cold Spring Harbor Laboratory.
- The master energy homeostasis regulator PGC-1α couples transcriptional co-activation and mRNA nuclear export, Cold Spring Harbor Laboratory.
- Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease, Cold Spring Harbor Laboratory.
- Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy.
- Acid Sphingomyelinase Deficiency Normalizes Neuronal Function in GCase Deficiency - Unexpected Biological Rescue Effect of Combined Genetic Risk Factors for Parkinson’s Disease, Research Square Platform LLC.
- Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons, Cold Spring Harbor Laboratory.
- A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation, Cold Spring Harbor Laboratory.
- Unexpected opposing biological effect of genetic risk factors for Parkinson’s disease, Cold Spring Harbor Laboratory.
- LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation, Cold Spring Harbor Laboratory.
- Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes inC9orf72ALS/FTD models. Life Science Alliance, 7(9), e202402853-e202402853.
- Research group
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Postdoctoral Research Associates
- Dr Francesco Capriglia
- Dr Naomi Hartopp
- Dr Alex Bury
- Dr Rachel Hughes
- Dr Katy Barnes
- Dr Orlaith O'Shaughnessy
- Dr Elezebeth Stephen
Research Assistants
- Nikolaos Stefanadis
- Ella Simmonite
PhD students
- James Lee
- Toby Burgess
- Louise Heywood
- Alicja Olejnik
- Rhiannon Brown
- Grants
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My research is currently funded by Parkinson’s UK Virtual Biotech, Cue Parkinson's, several industrial partners including Verge Genomics, NZP UK Ltd and Spark Therapeutics, and the Michael J Fox Foundation.
- Teaching activities
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I teach on the MSc courses in Translational Neuroscience, Translational Neuropathology, Clinical Neurology and Molecular Medicine focussing on protein assay work and basic cell biology assays, the pathogenetic mechanisms involved in Parkinson’s Disease and critical review of the literature teaching.
I also teach on the undergraduate Biomedical Science course on the module the Biological Basis of Brain Disease.
I enjoy training and supervising MSc and BMedSci students during their research projectsand usually host 2-3 students per year. In addition we host multiple medical students from the MBChB course for short projects per year.
- Professional activities and memberships
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I am a member of the Parkinson’s UK college of experts as well as the Patient Public Involvement Steering Group. I also sit on the Cure Parkinson’s Trust Review Panel.
I am lead external examiner for MRes courses at University of Newcastle. I regularly review for several funding bodies including MRC, Parkinson’s UK, BBSRC, Motor Neuron Disease Association, EU, ARUK and many others.
- Collaborators
Within Sheffield: Dr Laura Ferraiuolo, Prof Oliver Bandmann, Prof Kurt De Vos, Dr Suman De and Prof Val Gillet
Outside of Sheffield: Prof Sylvie Urbe (University of Liverpool), Prof Mike Clague (University of Liverpool), Dr Liz New (University of Sydney), Prof Joanna Poulton (University of Oxford), Dr Alex Whitworth (University of Cambridge)