Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome.

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological disorder that affects premutation carriers with 55-200 CGG-expansion repeats (preCGG) in FMR1, presenting with early alterations in neuronal network formation and function that precede neurodegeneration. Whether intranuclear inclusions containing DNA damage response (DDR) proteins are causally linked to abnormal synaptic function, neuronal growth and survival are unknown. In a mouse that harbors a premutation CGG expansion (preCGG), cortical and hippocampal FMRP expression is moderately reduced from birth through adulthood, with greater FMRP reductions in the soma than in the neurite, despite several-fold elevation of Fmr1 mRNA levels. Resting cytoplasmic calcium concentration ([Ca2+]i) in cultured preCGG hippocampal neurons is chronically elevated, 3-fold compared to Wt; elevated ROS and abnormal glutamatergic responses are detected at 14 DIV. Elevated µ-calpain activity and a higher p25/p35 ratio in the cortex of preCGG young adult mice indicate abnormal Cdk5 regulation. In support, the Cdk5 substrate, ATM, is upregulated by 1.5- to 2-fold at P0 and 6 months in preCGG brain, as is p-Ser1981-ATM. Bax:Bcl-2 is 30% higher in preCGG brain, indicating a greater vulnerability to apoptotic activation. Elevated [Ca2+]i, ROS, and DDR signals are normalized with dantrolene. Chronic [Ca2+]i dysregulation amplifies Cdk5-ATM signaling, possibly linking impaired glutamatergic signaling and DDR to neurodegeneration in preCGG brain.

• Authors: Gaëlle Robin, José R López, Glenda M Espinal, Susan Hulsizer, Paul J Hagerman, Isaac N Pessah
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 26 Issue 14 Pg. 2649-2666 (07 15 2017) ISSN: 1460-2083 [Electronic] England
• PMID: 28444183 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• FMR1 protein, human
• Fmr1 protein, mouse
• RNA, Messenger
• Fragile X Mental Retardation Protein
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Atm protein, mouse
• Cyclin-Dependent Kinase 5
• CDK5 protein, human
• Cdk5 protein, mouse
• Calcium

Topics

• Animals
• Ataxia (genetics, metabolism)
• Ataxia Telangiectasia Mutated Proteins (genetics, metabolism)
• Calcium (metabolism)
• Cyclin-Dependent Kinase 5 (genetics, metabolism)
• Disease Models, Animal
• Female
• Fragile X Mental Retardation Protein (genetics, metabolism)
• Fragile X Syndrome (genetics, metabolism)
• Hippocampus (metabolism, pathology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Neurons (metabolism, pathology)
• RNA, Messenger (metabolism)
• Tremor (genetics, metabolism)
• Trinucleotide Repeat Expansion