Skin cells from frontotemporal dementia patients may prove useful in
revealing disease mechanisms and in biomarker and drug research

Date:
August 12, 2021
Source:
University of Eastern Finland
Summary:
A new study suggests that skin fibroblasts from frontotemporal
dementia patients may be useful in investigating underlying disease
mechanisms as well as in biomarker and drug research.



FULL STORY ==========================================================================
A new study from the University of Eastern Finland suggests that skin fibroblasts from frontotemporal dementia patients may be useful in investigating underlying disease mechanisms as well as in biomarker and
drug research.


========================================================================== Frontotemporal dementia (FTD) is the second most common cause of
dementia in the working age population. The most common genetic cause
of FTD is the C9orf72 hexanucleotide repeat expansion. This expansion
is exceptionally common in Finnish FTD patients. Currently, there are
no efficient therapies for FTD, it is challenging to diagnose, and the
disease mechanisms remain largely unclear.

The new study explored whether skin cells from FTD patients, obtained
through skin biopsy performed at Kuopio University Hospital, show specific
cell pathological hallmarks or functional alterations compared to healthy individuals, which could promote better understanding of molecular
mechanisms of FTD and be useful in the discovery of novel biomarkers
or in testing drug effects. Both C9orf72 repeat expansion carriers and
patients with sporadic FTD, for whom the underlying cause of disease is unknown, were included in the study.

Cell pathological changes related to the C9orf72 repeat expansion have not
been widely described in other cells than neurons so far. In the present
study, skin fibroblasts of FTD patients carrying the C9orf72 expansion
were found to contain pathological RNA foci in the nuclei, which were
derived from the expanded repeat sequence. These findings indicate that
skin fibroblasts of carriers of the C9orf72expansion partially show
similar pathological changes to those found in the brain. Thus, patient
skin cell cultures may possess potential, for example, as platforms for
testing drug effects when screening compounds that could prevent formation
of the abnormal RNA foci and the subsequent pathological dipeptide repeat
(DPR) proteins derived from these abnormal RNAs.

The brains of FTD patients typically also show other pathological protein inclusions. The present study showed that in the skin fibroblasts of
both sporadic and C9orf72 expansion-carrying FTD patients, there were substantially more and larger p62 protein-containing vesicles than in
the healthy control fibroblasts. Accumulation of p62 could be a sign of defective ability of the cells to degrade proteins, but defects in the
function of the main cellular protein degradation routes, the proteasomes
or autophagosomes, were not detected in this study. On the other hand,
the present findings raise the question whether the increased number and
size of p62 vesicles in skin fibroblasts could be utilised as disease biomarkers in the diagnostics of FTD.

The current study also revealed that skin fibroblasts from both sporadic
and C9orf72expansion-carrying FTD patients displayed a significantly
weaker energy metabolism. These changes were detected in assays where
the basal respiration and ATP-mediated energy production by the cells'
power plants, the mitochondria, were measured. Because the defective
energy metabolism and the changes in p62 vesicles were detected in both sporadic and C9orf72expansion- carrying patients, these pathological alterations may represent common pathological changes in FTD patients regardless of their genetic background.

The changes observed in the skin fibroblasts are partially similar to
those observed in the brain of FTD patients.

"Because brain cells can rarely be obtained from the brains of living
patients, other patient-derived cells, such as skin fibroblasts, are
extremely useful in research. Their use enables clarifying disease
mechanisms at the cellular and molecular level, and may prove useful in biomarker or drug research, even at the individual level. In addition, patient-derived skin cells may be utilised as sources to produce
induced pluripotent stem cells (iPSCs), which in turn can be further differentiated in the laboratory to different types of brain cells and
used as human disease models in research,"explains Research Director
Annakaisa Haapasalo, in whose laboratory at the A.I. Virtanen Institute
for Molecular Sciences at the University of Eastern Finland the study
was conducted.

In the Haapasalo Lab, FTD patient-derived skin cells have also been
utilised to generate iPSCs and further differentiated to different
types of brain cells, such as neurons and microglia. Examination of
these cells is currently ongoing.

"It will be interesting to find out if similar cell pathological and
energy metabolism changes can be detected in the iPSC-derived neurons
or microglia produced from these skin fibroblasts,"says Postdoctoral
Fellow Dorit Hoffmann from the Haapasalo Lab, who is the co-first author
of the newly published study.

========================================================================== Story Source: Materials provided by University_of_Eastern_Finland. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Stina Leskela", Dorit Hoffmann, Hannah Rostalski, Nadine Huber,
Rebekka
Wittrahm, Pa"ivi Hartikainen, Ville Korhonen, Ville Leinonen, Mikko
Hiltunen, Eino Solje, Anne M. Remes, Annakaisa Haapasalo. FTLD
Patient- Derived Fibroblasts Show Defective Mitochondrial Function
and Accumulation of p62. Molecular Neurobiology, 2021; DOI:
10.1007/s12035- 021-02475-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210812092714.htm

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