We study the pathophysiology of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia by investigating inhibitory/excitatory changes in the affected neural circuits with the aim to find potential treatments and early indicators for pre-diagnosis.

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PRIMARY FIELDS OF RESEARCH

Neurodegenerative disorders, Amyotrophic lateral sclerosis and Frontotemporal dementia, mouse models of disease, systems neuroscience, machine learning-based behavioural assessment, spatial transcriptomics, gene therapy, in vitro disease modelling.

RESEARCH FOCUS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons found in spinal cord and brainstem, as well as cortico-spinal neurons. ALS is characterised by muscle wasting and progressive paralysis. Frontotemporal dementia (FTD) is a progressive neurodegenerative condition characterised by the degeneration of neurons in the frontal and temporal lobes, and by changes in behaviour and personality, frontal executive deficits and language dysfunctions. ALS and FTD have historically been considered unrelated neurodegenerative diseases, however it is now clear that genetic mutations in transactive response DNA-binding protein 43 (TARDBP), Fused-in-Sarcoma (FUS) and C9orf72 locus, are associated to both disorders and up to 50% of ALS cases develops FTD. These discoveries have transformed the approach to the investigations on disease mechanisms, however the origin and progression of ALS and FTD remain largely unknown and curative therapies do not exist. 

Dysfunctional cortical inhibition and changes in synaptic connectivity, leading to excitotoxicity, have been previously reported in both ALS and FTD (for review Mora & Allodi 2023, Frontiers in Neural Circuits). Moreover, our findings obtained in a mouse model of ALS (Allodi et al 2021, Nature Communications) showed loss of inhibitory inputs in the spinal cord already at asymptomatic stages. Loss of inhibitory inputs can lead to aberrant neuron excitability, intracellular ion dysregulation and cell death, extensively reported in ALS-FTD. However, the exact role of dysfunctional inhibition and changes in synaptic connectivity in disease onset and progression still remain unclear.

Machine learning-based behavioural analysis, system neuroscience approaches, spatial transcriptomics and multiplexing techniques, gene therapy are applied to understand the roles of interneuron connectivity in disease and to find new targets for treatment.