A New Angle for Ataxia and ALS Research

Nov 6, 2018
Author: 
Jim Oldfield

Professor Karim Mekhail, Amanda Hall and Lauren OstrowskiProfessor Karim Mekhail, Amanda Hall and Lauren Ostrowski Research from the University of Toronto has shown that in some neurodegenerative diseases, two hallmarks of cell aging — protein aggregation and a type of DNA instability, previously thought to be unconnected — are linked.

The researchers used cellular models of amyotrophic lateral sclerosis and spinocerebellar ataxia and found that the gumming up of certain proteins undermines the stability of ribosomal DNA repeats — repetitive genetic sequences essential for manufacturing all proteins and cells.

“We found that protein aggregates shorten the lifespan of the cell by compromising the stability of the highly repetitive ribosomal DNA sequences,” says Professor Karim Mekhail, who holds the Canada Research Chair in Spatial Genome Organization in the Department of Laboratory Medicine and Pathobiology. “That these two major mechanisms of cell aging are connected points to strategies that may hit two birds with one stone in neurodegeneration.”

The journal Communications Biology published the results yesterday.

Repetitive DNA sequences comprise over half of the genome in some organisms, and they are essential to cell function. But they are susceptible to re-organization, which can lead to chromosomal rearrangements, premature cell aging and disease.

Image by Roxanne OshidariTwo beasts of cellular aging, protein aggregation and genome instability, are one. Image by Roxanne Oshidari Mekhail and his team, including doctoral students Lauren Ostrowski and Amanda Hall, first found that trouble-making proteins — which emerge from repetitive DNA sequences called transposons — aggregate in yeast cells humanized with mutations found in patients suffering from ALS and ataxia. They then mapped how the aggregates destabilize ribosomal DNA repeats and lead to premature yeast cell aging, before confirming the findings in human cells.

The work took more than four years. “This story was full of surprises,” says Mekhail. “The findings may seem obvious in retrospect, but if you’d told us in the beginning that there was crosstalk between protein aggregation and destabilization of DNA, we’d have thought that was absurd. Lauren and Amanda really had to persevere.”

To identify new and urgently needed therapeutic approaches, the researchers are now testing if drugs that disrupt transposon protein aggregates restore genome stability and cell lifespan in various neurodegenerative diseases.

The research was funded by the Canada Research Chairs Program, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Ontario Ministry of Research and Innovation.

Tweets

UofT Medicine
@uoftmedicine
Illustration by Prof offers a nanoscale look at the COVID-19 particle https://t.co/XKhKSoQfOj
UofT Medicine
@uoftmedicine
RT : The only Black student in her class four years ago, 's Chika Oriuwa became an advocate for diversity in her fi… https://t.co/aoL7CGxfWz
UofT Medicine
@uoftmedicine
RT : -19 has amplified inequities in access & supports. These have real negative consequences for pat… https://t.co/aPyukrIdL7

Researchers are mobilizing against the novel SARS-CoV-2 coronavirus and COVID-19.

Make a gift and support their important work.
May 27 PGME Global Health Day 2020
Symposium | 1:00pm–6:00pm
May
29 – 30
RTi3 Conference 2020
Conference | 8:00am–5:00pm
May 30 15th Annual Arthritis Day for Primary Care Clinician
Conference | 7:45am–3:45pm
Jun 3 WebPac Training
Workshop/Seminar | 3:00pm–5:00pm
Jun
9 – 11
Teaching for Transformation: Summer Education Institute (SEI) program
Other | 9:00am–5:00pm
Jun
11 – 12
Target Insight 2020 -- Big Data: A Paradigm for Change
Conference | 8:30am–5:00pm
Jun 12 Medical Record-Keeping
Workshop/Seminar | 8:30am–4:30pm