Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases, part of a spectrum with overlapping pathology, impacting multiple brain regions and non-neuronal cell types beyond the characteristic motor and cortical neuron degeneration.
The striatum, an important integrative hub in the brain crucial for functions often impaired in FTD (e.g. behavioural and cognitive regulation, speech and language defects), exhibits dysfunction in FTD/ALS patients. Electrophysiological analysis revealed the first evidence of impaired medium spiny neuron (MSN) function. C9ORF72RE MSNs, harbouring the most common genetic mutation in FTD/ALS, displayed progressive hypoexcitability, abnormal action potential waveforms, impaired function of slow outwardly rectifying potassium (IK) channels and a potential shift in axon initial segment (AIS) positioning. MSN dysfunction may disrupt communication in brain networks, potentially explaining cognitive and behavioural symptoms in FTD/ALS patients. Targeting the discovered IK channel dysfunction and potential AIS changes offers promise for novel pharmaceutical intervention.
Astrocytes, essential for neuronal support, contribute to motor neuron death in ALS through a non-cell autonomous mechanism. The loss-of protective-function and gain-of-toxic-feature are likely caused by dysfunctional astrocyte membrane properties. Electrophysiological characterisation of C9ORF72RE astrocytes reveals membrane dysfunction due to connexin 43 (Cx43) dysregulation, mechanism which leads to astrocyte-mediated motor neuron toxicity, orchestrated in part by DPRs, and enhanced by environmental factors. This dysfunction expands to sporadic ALS, FTD and AD patients. Targeting astrocyte connexin dysfunction serves as a potential therapeutic target and
biomarker for ALS and other neurodegenerative diseases.
ORCID: https://orcid.org/0000-0003-3962-3531
(2024)
Exploring striatal neuron and astrocyte dysfunction in amyotrophic lateral sclerosis and frontotemporal dementia using stem cell technology and patch-clamp electrophysiology.
PhD thesis, University of Sheffield.
