Jeemen Sreedharan, M.D., Ph.D.
Dr Sreedharan developed an interest in neurodegeneration during his time as a medical student at King’s College London. Following medical training he conducted doctoral studies in the lab of Prof Christopher Shaw at the IoPPN, identifying TDP-43 mutations in patients with ALS. He then completed neurology training before obtaining an MRC Intermediate Clinical Fellowship to model TDP-43 mutations in vivo. The first two years of this Fellowship were spent at the University of Massachusetts Medical School, Worcester, USA. Here, he worked in the lab of Prof Marc Freeman to develop a novel method of screening for modifiers of TDP-43 toxicity using Drosophila melanogaster (the fruitfly). He also worked in the lab of Prof Robert H. Brown Jr to develop a novel TDP-43 knock-in mouse model of disease.
In 2014 Dr Sreedharan returned to the UK to work with Prof Michael Coleman at the Babraham Institute in Cambridge to continue his studies into TDP-43-mediated neurodegeneration. In June 2017 Dr Sreedharan set up an independent lab at the Maurice Wohl Clinical Neuroscience Institute thanks to a generous van Geest Post Doctoral Fellowship in Neurodegeneration Research. Using genetically engineered human stem-cell derived neurons and in vivo MRI to study the TDP-43Q331K knock-in mouse his lab hope to elucidate the causes and consequences of aberrant TDP-43 homeostasis in disease.
Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a ‘dying-back’ disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43Q331K, YFP-H double transgenic mouse. Sarm1 deletion attenuated motor axon degeneration and neuromuscular junction denervation. Motor neuron cell bodies were also significantly protected. Deletion of Sarm1 also attenuated loss of layer V pyramidal neuronal dendritic spines in the primary motor cortex. Structural MRI identified the entorhinal cortex as the most significantly atrophic region, and histological studies confirmed a greater loss of neurons in the entorhinal cortex than in the motor cortex, suggesting a prominent FTD-like pattern of neurodegeneration in this transgenic mouse model. Despite the reduction in neuronal degeneration, Sarm1 deletion did not attenuate age-related behavioural deficits caused by TDP-43Q331K. However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43Q331K mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43Q331K-mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD.