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Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.

ABSTRACT: Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson's disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1^-/-) mice. We now show that stimulation with physiological glutamate concentrations causes pathological [Ca²⁺]_c responses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca²⁺ uptake was reduced in gba1^-/- cells as was expression of the mitochondrial calcium uniporter. The rate of free radical generation was increased in gba1^-/- neurons. Behavior of gba1^+/- neurons was similar to gba1^-/- in terms of all variables, consistent with a contribution of these mechanisms to the pathogenesis of PD. These data signpost reduced bioenergetic capacity and [Ca²⁺]_c dysregulation as mechanisms driving neurodegeneration.

SUBMITTER: Plotegher N

PROVIDER: S-EPMC7206133 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.

Plotegher Nicoletta N Perocheau Dany D Ferrazza Ruggero R Massaro Giulia G Bhosale Gauri G Zambon Federico F Rahim Ahad A AA Guella Graziano G Waddington Simon N SN Szabadkai Gyorgy G Duchen Michael R MR

Cell death and differentiation 20191104 5

Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson's disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1<sup>-/-</sup>) mice. We now show that stimulation with physiological glutamate co ...[more]

PMID: 31685979

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Project description:Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment caused by dysfunction of inner hair cells, ribbon synapses, spiral ganglion neurons and/or the auditory nerve itself. Approximately 1/7000 newborns have abnormal auditory nerve function, accounting for 10%-14% of cases of permanent hearing loss in children. Although we previously identified the AIFM1 c.1265 G > A variant to be associated with ANSD, the mechanism by which ANSD is associated with AIFM1 is poorly understood. We generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) via nucleofection with episomal plasmids. The patient-specific iPSCs were edited via CRISPR/Cas9 technology to generate gene-corrected isogenic iPSCs. These iPSCs were further differentiated into neurons via neural stem cells (NSCs). The pathogenic mechanism was explored in these neurons. In patient cells (PBMCs, iPSCs, and neurons), the AIFM1 c.1265 G > A variant caused a novel splicing variant (c.1267-1305del), resulting in AIF p.R422Q and p.423-435del proteins, which impaired AIF dimerization. Such impaired AIF dimerization then weakened the interaction between AIF and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4). On the one hand, the mitochondrial import of ETC complex subunits was inhibited, subsequently leading to an increased ADP/ATP ratio and elevated ROS levels. On the other hand, MICU1-MICU2 heterodimerization was impaired, leading to mCa2+ overload. Calpain was activated by mCa2+ and subsequently cleaved AIF for its translocation into the nucleus, ultimately resulting in caspase-independent apoptosis. Interestingly, correction of the AIFM1 variant significantly restored the structure and function of AIF, further improving the physiological state of patient-specific iPSC-derived neurons. This study demonstrates that the AIFM1 variant is one of the molecular bases of ANSD. Mitochondrial dysfunction, especially mCa2+ overload, plays a prominent role in ANSD associated with AIFM1. Our findings help elucidate the mechanism of ANSD and may lead to the provision of novel therapies.

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Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.

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Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.

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