Delineating selective vulnerability of inhibitory interneurons in Alpers' syndrome

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.

Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction

“…One study reported an association between the loss of PV+ neurons in the entorhinal cortex with neuropathological amyloid-β and tau burden [ 134 ]. Loss of PV expression has been reported in DLB post-mortem hippocampal tissue [ 12 ], and in primary visual cortical areas [ 135 ], which is similar to our observations in PMDs [ 18 , 19 ], while others found no changes [ 136 ]. However, many factors including the brain region studied, sex and disease stage could all contribute to the differences reported.…”

“…Stroke-like episodes in PMDs are subacute-onset evolving encephalopathic episodes associated with neurological and/or psychiatric symptoms, which are hypothesised to be driven by focal seizure activity [ 52 , 59 , 60 ]. Although the mechanisms underpinning epilepsy in PMDs have not been fully elucidated, there is mounting evidence demonstrating dysfunction of inhibitory interneurons and glial cells is implicated in neuronal hyperexcitability and seizure generation [ 17 , 18 , 61 , 62 ].…”

“…Interestingly, comparison of the levels of OXPHOS protein deficiencies between neuronal subtypes revealed a more pronounced deficiency in inhibitory neurons compared with glutamatergic excitatory neurons in Alpers’ syndrome, a rare paediatric mitochondrial disease [ 63 ], thus suggesting a specific vulnerability of inhibitory neurons to metabolic impairment in PMD. Furthermore, a more recent study delineating the vulnerabilities of specific inhibitory neuron subtypes in Alpers’ syndrome revealed a preponderance of PV+ cortical neurons to degeneration [ 18 ]. Extensive OXPHOS protein deficiencies, indicative of mitochondrial dysfunction, were observed within remaining PV+ neurons and were more severe in comparison to CR+ neurons [ 18 ].…”

“…Furthermore, a more recent study delineating the vulnerabilities of specific inhibitory neuron subtypes in Alpers’ syndrome revealed a preponderance of PV+ cortical neurons to degeneration [ 18 ]. Extensive OXPHOS protein deficiencies, indicative of mitochondrial dysfunction, were observed within remaining PV+ neurons and were more severe in comparison to CR+ neurons [ 18 ]. These findings suggest not only the preferential susceptibility of inhibitory neurons to dysfunction and degeneration in PMD, but also support the idea that PV+ neurons are particularly vulnerable to metabolic impairment, and thus likely have an important role in mitochondrial epilepsy.…”

Hallmark Molecular and Pathological Features of POLG Disease are Recapitulated in Cerebral Organoids

“…Our study not only revealed the loss of neurons but also highlighted the presence of astrocyte activation and reactive gliosis in patient‐derived organoids. The observed astrocyte activation is particularly significant as it has been shown in our study [ 26 ] and previous research [ 34–36 ] to be associated with neuronal toxicity and may contribute to the neural loss observed in POLG‐related disorders. Astrocytes play crucial roles in supporting neuronal function and maintaining brain homeostasis.…”