Objective: We aimed to document the alterations of pathways and molecules that underlie brain pathology in the Perrault syndrome.

Background: Perrault syndrome is an autosomal recessively inherited rare disorder with early sensorineural deafness, accompanied by complete infertility and progressive cerebellar ataxia. Loss-of-function mutations in the CLPP (Caseinolytic Mitochondrial Matrix Peptidase Proteolytic Subunit) gene are responsible. Although this peptidase is highly conserved from bacteria until the mitochondrial matrix of human species, the protein substrates that are cleaved by CLPP rather than by the other two mitochondrial matrix proteases (LONP1 and m-AAA, the latter being responsible for Spinocerebellar Ataxia type 28) are still unclear.

Methods: Clpp-knock-out (KO) mouse brains were dissected and subjected to global proteome profiling via label-free mass spectrometry and volcano plot analysis. Biomathematical workup was carried out with the STRING webserver in Heidelberg. Validation experiments included quantitative reverse-transcriptase polymerase chain reactions and immunoblots.

Results: A systematic accumulation of practically all mitoribosomal subunits was observed, in the absence of transcriptional induction, suggesting decreased turnover of the mitoribosomal proteins in the absence of CLPP peptidase. The molecular chaperone ERAL1 in the mitochondrial matrix is involved in mitoribosomal assembly and showed protein accumulation in the absence of transcriptional induction, as well. These data confirm analogous observations of an independent team in Clpp-KO heart tissue, which were recently published (Szczepanowska K et al 2016 EMBO J) and also showed mitoribosome and ERAL1 accumulation.

Conclusions: The mitoribosomal dysregulation in Clpp-deficient neural tissue is likely to explain the progressive hearing impairment in Perrault syndrome. Previous observations of mitochondrial rRNA and tRNA variants as the cause of sensorineural deafness point in the same direction. Mitoribosomes are also the target of aminoglycoside antibiotics, which cause deafness upon chronic administration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/perrault-syndrome-clpp-knock-out-mouse-brain-shows-accumulation-of-mitoribosomes/