Professor Majid Hafezparast

Mechanisms of neurodegenerative disease

Neurodegenerative diseases consist of a large, varied group of pathologies, characterised by the degeneration of specific subsets of neurons and they include pathologies often seen in the elderly.

In Motor Neurone Diseases (MND) such as Amyotrophic Lateral Sclerosis (ALS), the age of people who develop ALS is between 40 and 70 years old. With an ever-increasingly aging population the socio-economic cost of these conditions is rising as neurodegenerative diseases affect more and more people. In the case of ALS the lifetime risk of succumbing to the disease is 1 in 300. Moreover, people with ALS, the most common form of adult-onset MND, die within 2-5 years after appearance of the symptoms.
There are several areas of research we are currently undertaking in which new projects could be developed to further our understanding of neurodegenerative disease. One area is seeking to answer the longstanding question of whether age-related reduction in the function of cytoplasmic dynein, a molecular motor responsible for transport in neurons, predisposes neurons to dysfunctional protein degradation and consequently accumulation of toxic misfolded protein aggregates, leading to neuronal cell death in neurodegenerative disease. We have evidence to support this and we are looking further to see whether when combined with minor mutations in MND-related genes, it can lead to development of MND (the multiple-hit hypothesis). This project will use a range of cell and molecular biology techniques in combination with advanced microscopy to investigate the underlying molecular mechanisms that lead to the demise of motor neurons in MND.

Another project will be in the area of non-coding RNA (ncRNA) in MND, based on their use as potential biomarkers of MND. Biomarkers are increasingly regarded as important components for successful development and trialling of new treatments for any neurodegenerative disease. Additionally, they could provide much needed certainty to people with MND and their families by helping to reduce the delay in providing a diagnosis through the administration of a simple blood test, as well as providing an indication and prediction of the disease progression. Based on our results, we are improving our initial nc-RNA biomarker signature as well as looking at the source of these ncRNA and their role in the disease pathology. This project utilises next generation RNA-seq technology combined with molecular biology techniques including RT-qPCR, in combination with bioinformatics tools to analyse, seek and identify dysregulated ncRNAs such as microRNAs which could be used as biomarkers of MND.

Another area of interest in the Hafezparast Laboratory is the role of the microglia-derived ncRNA in the pathogenesis of MND. Microglia are the immune cells of the nervous system that play crucial roles in synaptic maintenance and in protecting the central nervous system from pathogens. They also contribute to neuroinflammation in neurodegenerative disease and there is growing evidence that they play critical roles in the development of MND. We have evidence that microglia release, in addition to cytokines, ncRNAs which can potentially affect gene expression in neurons and consequently cause them to become dysfunctional. We are currently utilising RNA-seq, RT-qPCR and bioinformatics and cell/molecular biology techniques to identify the targets and impact of microglia-derived ncRNA on motor neurons and their contribution to MND.

Key references

• Joilin G, Gray E, Thompson AG, Talbot K, Leigh PN, Newbury SF, Turner MR, Hafezparast M. (2022). Profiling non-coding RNA expression in cerebrospinal fluid of amyotrophic later sclerosis patients. Ann Med. 2022 Dec;54(1):3069-3078. doi: 10.1080/07853890.2022.2138530. PMID: 36314539
• Joilin G, Gray E, Thompson AG, Bobeva Y, Talbot K, Weishaupt J, Ludolph A, Malaspina A, Leigh PN, Newbury SF, Turner MR, Hafezparast M. (2020). Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis. Brain Commun. 2020;2(1):fcaa053. doi: 10.1093/braincomms/fcaa053. Epub 2020 Jun 17. PMID: 32613197 Free PMC article.
• Christoforidou E, Joilin G, Hafezparast M. (2020). Potential of activated microglia as a source of dysregulated extracellular microRNAs contributing to neurodegeneration in amyotrophic lateral sclerosis. J Neuroinflammation. 2020 Apr 28;17(1):135. doi: 10.1186/s12974-020-01822-4. PMID: 32345319 Free PMC article. Review.
• Joilin G, Leigh PN, Newbury SF, Hafezparast M (2019). An Overview of MicroRNAs as Biomarkers of ALS. Front Neurol. 2019 Mar 7;10:186. doi: 10.3389/fneur.2019.00186. eCollection 2019. PMID: 30899244 Free PMC article. Review.
• De Vos KJ, Hafezparast M (2017). Neurobiology of axonal transport defects in motor neuron diseases: Opportunities for translational research? Neurobiol Dis. 2017 Sep;105:283-299. doi: 10.1016/j.nbd.2017.02.004. Epub 2017 Feb 22. PMID: 28235672 Free PMC article. Review.
• Garrett CA, Barri M, Kuta A, Soura V, Deng W, Fisher EM, Schiavo G, Hafezparast M (2014). DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos signalling in a mouse model of distal spinal muscular atrophy. Brain. 2014 Jul;137(Pt 7):1883-93. doi: 10.1093/brain/awu097. Epub 2014 Apr 22. PMID: 24755273
• Schiavo G, Greensmith L, Hafezparast M, Fisher EM. (2013). Cytoplasmic dynein heavy chain: the servant of many masters. Trends Neurosci. 2013 Nov;36(11):641-51. doi: 10.1016/j.tins.2013.08.001. Epub 2013 Sep 10. PMID: 24035135 Free PMC article. Review.
• Hafezparast M, Klocke R, Ruhrberg C, et al (2003). Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science. 2003 May 2;300(5620):808-12. doi: 10.1126/science.1083129. PMID: 12730604

Visit the Hafezparast Lab pages for more details and a full list of publications.

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