A gene mutation causing Purkinje cell degeneration and ataxia-like symptoms in a mouse model has been identified by a team of scientists. The team, led by Dr Marija Kojic and Professor Brandon Wainwright from The University of Queensland’s Institute for Molecular Bioscience (IMB) and Dr Sebastian Glatt from Jagiellonian University in Krakow, made the findings in a study of cerebellar ataxias.

Cerebellar ataxias are caused by damage to the cerebellum, the part of the brain that controls motor function.

“These rare but devastating conditions get worse over time, causing poor coordination, unsteady walking, difficulty speaking and swallowing, and difficulty performing fine motor skills such as buttoning a shirt. While they are often caused by environmental factors such as alcohol, these conditions also have genetic causes, which have so far been largely unexplored. For the first time, we have found a link between ataxias and a mutation of the Elongator gene, which regulates how our brain cells produce proteins,"

Dr Kojic explained.

Neurological Degeneration

The researchers discovered this mutation slows production of the proteins that neurons need to function, causing them to gradually degenerate.

[caption id=“attachment_96926” align=“aligncenter” width=“680”]lp6L126Q destabilizes Elp456. lp6L126Q destabilizes Elp456.
(a) Structural overview of the Elongator complex in cartoon representation showing individual subunits (Elp1 (orange), Elp2 (yellow), Elp3 (pink), Elp4 (green), Elp5 (blue), and Elp6 (brown)) from two perspectives.
The Elp6L126Q mutation is highlighted in red (triangles). Multiple sequence alignment of Elp6 proteins from S. cerevisiae (Q04868), M. musculus (Q8BK75), and H. sapiens (AAH00623) highlighting the mutated region (bottom).
(b) SDS-PAGE analyses after size exclusion chromatography (SEC) of purified Elp456 complexes from yeast (top), mouse wild-type (middle) and mouse Elp6L126Q (bottom). Subunits are labeled on the right and co-migrating chaperone is indicated by an asterisk.
(c) same as (a) highlighting the localization of the hexameric Elp456 ring and the mutation (top). Normalized first derivative curves from Thermofluor analyses of purified yElp466-42651-2706 (black), mElp449-38956 (orange), and mElp449-38951-2506 (red) complexes.
Wild-type complexes are shown by lines, mutations (L126Q for mouse and L130Q for yeast) are labeled with black circles, copurified contaminations are shown in gray. Calculated melting temperatures are indicated.
(d) Quantification of ncm5U, mcm5U, s2U, and m7G nucleosides in cerebellar lysates from wobbly and wild-type animals analyzed using HPLC/MS (n = 5 animals per genotype).
Credit: Marija Kojic et al. CC-BY[/caption]

Professor Wainwright said the team also uncovered a link between inflammation of brain cells and brain degeneration, including ataxias.

“Our study revealed inflammation in the cells surrounding the degenerated cells. While this is not unusual, we found that blocking this inflammation slowed the rate at which the cells were dying. This effect occurs across a broad range of neuro-degenerative conditions, such as Alzheimer’s disease, Parkinson’s disease and motor neurone disease, which has profound implications for the treatment of these diseases.

We may not be able to stop this neurological degeneration but if we can slow it down – for example, so a disease takes 20 years to progress, rather than 10 – this could have a huge impact on the health and quality of life of people living with these conditions,"

Wainwright said. Ataxias are progressive and currently incurable disorders, but this research offers hope for the future.

The work was supported by a grant from the National Science Centre, Poland, funding from the European Union’s Horizon 2020 research and innovation program, and from the Foundation for Polish Science.

Marija Kojic, Monika Gaik, Bence Kiska, Anna Salerno-Kochan, Sarah Hunt, Angelo Tedoldi, Sergey Mureev, Alun Jones, Belinda Whittle, Laura A. Genovesi, Christelle Adolphe, Darren L. Brown, Jennifer L. Stow, Kirill Alexandrov, Pankaj Sah, Sebastian Glatt & Brandon J. Wainwright Elongator mutation in mice induces neurodegeneration and ataxia-like behavior Nature Communications volume 9, Article number: 3195 (2018)

Top Image: Ataxia and neurodegeneration in wobbly mice. a Left: hindlimb clasping in wild-type and mutant animals. Right: behavioral analysis of the wobbly phenotype relative to wild-type (n = 10 (5 males and 5 females) for each of the genotypes; homozygous wobbly animals are presented as wobbly and heterozygous as wobbly het). b H&E staining of P60 cerebellar sagittal. Arrows indicate PN loss, and circles mark degenerating PNs. Black rectangles represent magnified areas. c Pcp2 immunofluorescence and PN quantification in wobbly and wild-type cerebella. d Representative raw traces of train of action potentials in PNs elicited by current injections of 50 and 100 pA in wild-type and wobbly cells, respectively. e Resting membrane potential of wobbly (−40.9 ± 1.2 mV, n = 10) and wild-type (−47.3 ± 1.4 mV, n = 18) PNs at P21–24. f Number of action potentials of wobbly (n = 10) and control (n = 13) PNs at threshold elicited by current injections. For (b) and (c) n = 5 for each of the genotypes and ages presented; representative images are shown. Scale bars: (b) left panel, (c) 500 μm; (b) middle panel, 100 μm; (b) right panel, 50 μm. Statistical evaluation: (a, c) two-way ANOVA and Sidak’s multiple comparisons test; (e, f) two-tailed t test. Statistically significant differences are indicated (*P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.0001). Data represent mean ± SEM. Credit: Marija Kojic et al. CC-BY

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