Delineating selective vulnerability of inhibitory interneurons in Alpers' syndrome. (19th July 2022)

• Record Type: Journal Article
• Authors: Smith, Laura A.; Erskine, Daniel; Blain, Alasdair; Taylor, Robert W.; McFarland, Robert; Lax, Nichola Z.
• Is Part Of: Neuropathology & applied neurobiology. Volume 48:Number 6(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-19
• Subjects: Alpers' syndrome -- calretinin -- inhibitory interneurons -- mitochondrial epilepsy -- parvalbumin -- POLG -- seizures; Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12833
• Languages: English
• ISSNs: 0305-1846

Abstract

Abstract: Aims: Alpers' syndrome is a severe neurodegenerative disease typically caused by bi‐allelic variants in the mitochondrial DNA (mtDNA) polymerase gene, POLG, leading to mtDNA depletion. Intractable epilepsy, often with an occipital focus, and extensive neurodegeneration are prominent features of Alpers' syndrome. Mitochondrial oxidative phosphorylation (OXPHOS) is severely impaired with mtDNA depletion and is likely to be a major contributor to the epilepsy and neurodegeneration in Alpers' syndrome. We hypothesised that parvalbumin‐positive(+) interneurons, a neuronal class critical for inhibitory regulation of physiological cortical rhythms, would be particularly vulnerable in Alpers' syndrome due to the excessive energy demands necessary to sustain their fast‐spiking activity. Methods: We performed a quantitative neuropathological investigation of inhibitory interneuron subtypes (parvalbumin+, calretinin+, calbindin+, somatostatin interneurons+) in postmortem neocortex from 14 Alpers' syndrome patients, five sudden unexpected death in epilepsy (SUDEP) patients (to control for effects of epilepsy) and nine controls. Results: We identified a severe loss of parvalbumin+ interneurons and clear evidence of OXPHOS impairment in those that remained. Comparison of regional abundance of interneuron subtypes in control tissues demonstrated enrichment of parvalbumin+ interneurons in the occipital cortex, while other subtypes did not exhibit such topographic specificity. Conclusions: These findings suggest that the vulnerability of parvalbumin+ interneurons to OXPHOS deficits coupled with the high abundance of parvalbumin+ interneurons in the occipital cortex is a key factor in the aetiology of the occipital‐predominant epilepsy that characterises Alpers' syndrome. These findings provide novel insights into Alpers' syndrome neuropathology, with important implications for the development of preclinical models and disease‐modifying therapeutics. Abstract : Alpers' syndrome is a severe mitochondrial disease characterised by intractable epilepsy and extensive neurodegeneration. Our neuropathological study has revealed an increased vulnerability of parvalbumin‐positive inhibitory interneurons to dysfunction and degeneration in Alpers' syndrome which likely underlies the severe occipital‐predominant epilepsy in patients with Alpers' syndrome. These findings have important implications for the development of preclinical models of Alpers' syndrome neuropathology and disease‐modifying therapeutics.