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A NEW MITOCHONDRIAL GENE CAUSING NEURODEGENERATION AND AMYLOID DEPOSITION IN THE BRAIN

In this study we established for the first time a direct link between an altered mitochondrial function and amyloid neurodegeneration. 

In this collaborative study, we described the first family with a (recessive) pathological mutation in the gene encoding PITRM1, the mitochondrial matrix metallopeptidase that digests mitochondrial targeting sequences after cleavage by the mitochondrial matrix peptidase. The PITRM1 mutation was associated with a slowly progressive neurodegenerative condition characterized by mild mental retardation, spinocerebellar ataxia with cerebellar atrophy and psychosis.

We confirmed the pathogenicity of the mutation by investigating mutant and RNAi cells, and a yeast model (the yeast ortholog is CYM1). In vitro assays carried out on the recombinant protein expressed in E. coli, led us to conclude that the mutation causes severe protein instability mimicking a condition of haploinsufficiency. Investigations of a Pitrm1-/+ mouse model (the Pitrm1-/- individuals are embryonic lethal), also showed reduced Pitrm1 protein in different tissues and the animals developed a progressive neurological syndrome characterized by ataxia, behavioural impairment and abnormal bioenergetics parameters in vivo.

Interestingly, neuropathological investigation of these animals revealed the accumulation of Amyloid Precursor Protein and amyloid beta (Aβ) deposits, similar to the amyloid plaques seen in Alzheimer's disease brains (see figure). The accumulation of Aβ supports the hypothesis that PITRM1 is involved in the quantitative digestion of a fraction of Aβ and that this protein product is indeed contained within mitochondria. This observation has been controversial and our findings confirm this for the first time in a mammalian model.

This work was a collaboration between groups from Norway (Bergen - MMN & Center for Medical Genetics and Molecular Medicine; Førde), UK (MBU, Cambridge), Italy (Rome, Parma) and Sweden (Stockholm)

https://www.ncbi.nlm.nih.gov/pubmed/26697887

Fig.1
Photo:
from Pubmed

 

 

 

 

NEW DISSERTATION IN SEPTEMBER 2020

Omar Hikmat presented his dissertation for the Ph.D. degree with the thesis "The phenotypic spectrum of polymerase gamma (POLG) disease from birth to late adulthood" on September 25th 2020. The main supervisor for this thesis was Professor Laurence A. Bindoff and co-supervisor was Professor Charalampos Tzoulis

Omar Hikmat
Photo:
Omar Hikmat, photo is from UiB website.

 

NEWS ON STEM CELL STUDY

Using stem cell technology, our group have managed to reconstruct disease progression in mitochondrial failure. This can be a step towards the treatment of severe epilepsy and other brain diseases.Our group have managed to reconstruct disease progression in mitochondrial failure. This can be a step towards the treatment of severe epilepsy and other brain diseases. The study is published in EMBO Molecular Medicine.  

 

NSC paper
Photo:
from EMBO mol. med.

 

6th BSCC ANNUAL MEETING

Our group has attended the 6th Bergen Stem cell Consortium (BSCC) annual meeting in Solstrand Hotel & Bad on 19-20, October 2019. , This is a networking event with basic and clinical research update in the field of stem cells and regenerative medicine. Senior reseacher Kristina Xiao Liang presented a talk on “Using induced pluripotent stem cells (iPSCs) to model mitochondrial disease, study tissue specific manifestations and investigate treatments”. Postdoc. Yu Hong and PhD fellows Cecilie, Sepideh and Anbin gave a lightning talk in the meeting. 

6th annual meeting
Photo:
Lightning talk section, photo is from Kristina Xiao Liang.

NEW PUBLICATION ON CARDIOMYOCYTE DIFFERENTIATION FROM IPSCS

Out group has recently published a new paper on “A method for differentiating human induced pluripotent stem cells toward functional cardiomyocytes in 96-well microplates”. In this study, Novin Balafkan (first author) and Sepideh Mostafavi (co-first author) et al. developed a protocol for efficient differentiation towards cardiomyocytes from iPSCs using defined, serum-free culture medium combined with small molecules. We believe that this technique will improve the applicability of these cells for use in developmental biology and mechanistic studies of disease.The study is published in Scientific Report. 

Novin paper
Photo:
from Scientific Report

 

NEW POSTDOC. FELLOW 

Congratulations to Dr. Yu Hong, who will start his new adventure in working as a post-doctoral fellow in MMN group. He will be working on iPSC-derived 3D human brain organoids to study POLG diseases.

 

Yu Hong
Photo:
from UiB website

 

5th BSCC ANNUAL MEETING

As one of the research groups in Bergen Stem Cell Consortium (BSCC). We have organized and attended the 5th BSCC annual meeting in Hotel Scandic Ørnen on 3-4, October 2019.

5TH BSCC
Photo:
from UiB website