Ph.D. Defense by Michael Sloth Trabjerg

Michael Sloth Trabjerg will defend his Ph.D. thesis “ Carnitine palmitoyl transferase 1 – A potential target to restore dysregulated metabolism in neurodegenerative diseases? Based on in vivo models mimick-ing amyotrophic lateral sclerosis, Parkinson´s disease and multiple sclerosis”

Time

26.02.2021 kl. 13.00 - 16.00

Description

PROGRAM

13.00 Opening by the Moderator Jacek Lichota  
13.05 PhD lecture by Michael Sloth Trabjerg
13.50 Break
14.00 Questions and comments from the Committee
          Questions and comments from the audience at the Moderator’s discretion
16.00 Conclusion of the session by the Moderator

 

EVALUATION COMITEE

The Faculty Council has appointed the following adjudication committee to evaluate the thesis and the associated lecture: 

 

Albert Gjedde, Professor of Translational Neurobiology, Department of Clinical Research, University of Southern Denmark

Jean-Philippe Loeffler, Head of  Central and Peripheral Mechanisms of Neurodegeneration Laboratory, University of Strasbourg, France

Chairman:

Associate Professor Claudia Christine Hilt Kristensen, HST, Aalborg Universitet

Moderator:

Associate Professor Jacek Lichota , HST, Aalborg Universitet

 

ABSTRACT

In the last century, neurological disorders have been recognized as individual entities and categorized by their pathological characteristics’ such as motor neuron disease, neurodegenerative or demyelinating. However, in the last decades, it has become clear that they share several common pathogenic mechanisms, and that most central nervous system diseases have disruption of homeostasis in multiple systems outside the central nervous system. The neurodegenerative diseases amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and multiple sclerosis (MS) are all characterized by inflammation, oxidative stress, mitochondrial dysfunction, dysregulated hypothalamic-pituitary-adrenal axis and pathological changes in the gut microbiota. Additionally, in ALS, PD and MS the metabolism is dysregulated, characterized by a shift from the metabolism of glucose to the metabolism of lipids. The CNS utilises glucose as its primary fuel but under pathological conditions, the metabolism can shift towards lipid metabolism. Lipid metabolism promotes a variety of pathological processes such as inflammation, oxidative stress and mitochondrial dysfunction. The gate-keeper of the metabolism of lipids is carnitine palmitoyl transferase 1 (CPT1), which is located at the outer mitochondrial membrane and facilitates the transport of long-chain fatty acids into the mitochondrial matrix. In the mitochondrial matrix, fatty acids undergo β-oxidation to form acetyl-CoA that subsequently can generate ATP through the Krebs cycle and electron transport chain. However, the acetyl-CoA from the β-oxidation exerts negative feedback to glucose metabolism, which establishes a vicious cycle promoting lipid metabolism.

Manuscript I presents data illustrating the beneficial clinical and molecular effects of downregulating CPT1 activity by pharmacological and genetic mechanisms in the SOD1 G93A in vivo models mimicking ALS. Further, I present harmful effects of stimulating lipid metabolism through high fat diet.

Manuscript II presents data illustrating the beneficial clinical and molecular effects of downregulating CPT1 activity by pharmacological and genetic mechanisms in the rotenone and Park2 in vivo models mimicking PD.

Manuscript III presents data illustrating that Cpt1a mutated mice are resistant to induction with experimental autoimmune encephalomyelitis (EAE) and that high fat diet exacerbate disease in wild type but not Cpt1a mutated mice. 

Manuscript IV presents data illustrating that pharmacological inhibition of CPT1 results in changes in autoantibody-brain-antigen recognition in an EAE rat model, which is consistent with diminished disease activity compared to placebo and the first-line treatment interferon-β. 

Manuscript V presents a systemic platform for how the pathogenic mechanisms in neurodegenerative diseases such as ALS, PD and MS all are linked to a disruption of metabolic homeostasis based on data from the SOD1 G93A, rotenone and EAE models.

This indicates that neurodegenerative diseases have to be recognized from a systemic perspective where dysregulated metabolism plays a pivotal role in the etiology and progression of neurodegenerative diseases like ALS, PD and MS. In addition, the results indicate that modulation of the metabolism, possibly through CPT1, could be a key target in the treatment of neurodegenerative diseases.    

Host

Department of Health Science and Technology

Address

Ph.D. Defense take place via Zoom. A Zoom link will be sent to registered attendees prior to the defense via an Outlook invitation.

Registration Deadline

24.02.2021 kl. 12.00

Register at

lkkr@hst.aau.dk

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