Summary: A new study identifies a genetic mutation as an additional cause of cerebellar ataxia.
Source: Cell Press.
Cerebellar ataxia is a condition of the cerebellum that causes an inability to coordinate muscle movements. A study publishing June 16 in Cell Reports now describes a new genetic mutation as an additional cause of ataxia in humans and mice. The mutation, in the gene CAPN1, affects the function of the enzyme calpain-1 and causes abnormal brain development. The same genetic mutation is also associated with ataxia in Parson Russell Terrier dogs.
“There are a number of genes linked to motor function that can be involved in ataxia when mutated,” says Michel Baudry, a neurobiologist at Western University of Health Sciences. “Not only have we identified another, but we’ve also refined our understanding of the calpain enzymes, which is important because several companies have been talking about using calpain inhibitors to treat neurodegenerative diseases.”
Calpain is an enzyme involved with learning, memory, and neurodegeneration in the brain, but it comes in two major forms–calpain-1 and calpain-2. “Nobody could make much progress on figuring out what each form of calpain was doing, because most of the pharmacological studies used molecules that inhibit both types at once” says Baudry. But about eight years ago, Baudry’s team obtained a line of mice genetically engineered to lack only calpain-1 to examine the differences.
Baudry’s mouse studies caught the attention of Henry Houlden, a neurologist at University College London, who was leading a team investigating ataxia. “Around two years ago, we identified two families with CAPN1 mutations with ataxia and spasticity,” Houlden explains. Once the researchers determined that the mutation affected calpain-1’s function, they looked up Baudry’s work on the calpain-1 knockout mice. “Together, we started to investigate the function of this gene,” says Houlden. The current study includes four families with members that have CAPN1 mutations and display symptoms of ataxia.
Baudry’s team started testing whether the knockout mice had ataxia by tracking their balance when placed on a rotating rod. “We had never looked at the cerebellum in our mice before,” says Baudry. “But sure enough, we found that they had mild cerebellar ataxia.”
The researchers demonstrated that during the first week after birth, the mice lacking calpain-1 had a much higher rate of neuronal death in their cerebellum, as compared to normal mice, and many of their synapses failed to mature.
“Calpain-1 is neuroprotective,” explains Baudry. “When the brain matures, excess neurons are supposed to be pruned–but calpain-1 prevents that process from getting out of control.” The team further determined that calpain-1 works normally by degrading an enzyme called PHLPP1, a protein phosphatase involved in programmed cell death. Injecting another compound involved in the pathway during the first postnatal week caused the newborn mice with CAPN1 mutations to develop normally.
Pharmacologically, the attempts to use calpain inhibitors in the clinic may not be working because they don’t discriminate between calpain-1 and calpain-2, says Baudry: “If you want to try to address neurodegeneration, you have to use a calpain-2 inhibitor.” Baudry is currently working with a team to develop calpain-2 inhibitors as neuroprotective drugs, under the umbrella of a new company called NeurAegis.
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Source: Joseph Caputo – Cell Press Image Source: This NeuroscienceNews.com image is credited to Wang et al./Cell Reports 2016. Original Research: Full open access research for “Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans” by Yubin Wang, Joshua Hersheson, Dulce Lopez, Monia Hammer, Yan Liu, Ka-Hung Lee, Vanessa Pinto, Jeff Seinfeld, Sarah Wiethoff, Jiandong Sun, Rim Amouri, Faycal Hentati, Neema Baudry, Jennifer Tran, Andrew B. Singleton, Marie Coutelier, Alexis Brice, Giovanni Stevanin, Alexandra Durr, Xiaoning Bi, Henry Houlden, and Michel Baudry in Cell Reports. Published online June 16 2016 doi:10.1016/j.celrep.2016.05.044
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]Cell Press. “Genetic Mutation Causes Ataxia in Humans and Dogs.” NeuroscienceNews. NeuroscienceNews, 17 June 2016. <https://neurosciencenews.com/genetics-ataxia-neurology-4505/>.[/cbtab][cbtab title=”APA”]Cell Press. (2016, June 17). Genetic Mutation Causes Ataxia in Humans and Dogs. NeuroscienceNews. Retrieved June 17, 2016 from https://neurosciencenews.com/genetics-ataxia-neurology-4505/[/cbtab][cbtab title=”Chicago”]Cell Press. “Genetic Mutation Causes Ataxia in Humans and Dogs.” https://neurosciencenews.com/genetics-ataxia-neurology-4505/ (accessed June 17, 2016).[/cbtab][/cbtabs]
Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans
Highlights •Null calpain-1 mutations result in cerebellar ataxia in humans and mice •Ataxia is due to altered cerebellar development and adult function •Calpain-1-mediated truncation of PHLPP1 and Akt activation limits postnatal apoptosis •Pharmacologic or genetic Akt activation reverses developmental alterations and ataxia
Summary A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.
“Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans” by Yubin Wang, Joshua Hersheson, Dulce Lopez, Monia Hammer, Yan Liu, Ka-Hung Lee, Vanessa Pinto, Jeff Seinfeld, Sarah Wiethoff, Jiandong Sun, Rim Amouri, Faycal Hentati, Neema Baudry, Jennifer Tran, Andrew B. Singleton, Marie Coutelier, Alexis Brice, Giovanni Stevanin, Alexandra Durr, Xiaoning Bi, Henry Houlden, and Michel Baudry in Cell Reports. Published online June 16 2016 doi:10.1016/j.celrep.2016.05.044