Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration

Departments of Neurosurgery, Neurobiology, Genetics, Program on Neurogenetics, Diagnostic Radiology, Neurology, Molecular, Cellular, and Developmental Biology, and Pharmacology, and Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2013; DOI: 10.1073/pnas.1222732110
Source: PubMed


Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.

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    • "Lastly, in 2013 three siblings from a Turkish family were discovered with a recessive, missense mutation in the Ub-binding domain of UCHL1 (mutation E7A), which leads to markedly reduced catalytic activity of this DUB in vitro. Patients from this family show an early-onset progressive neurodegenerative syndrome that includes cerebellar ataxia, spasticity, blindness, and nystagmus (Bilguvar et al., 2013). These symptoms are different from those of PD patients, including the ones who carry the I93M mutation. "
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    • "A different mutation was found in a rare progressive neurodegenerative disease (Bilguvar et al., 2013). Both mutations lead to the creation of a loss of function protein (Leroy et al., 1998; Bilguvar et al., 2013), indicating that proper de-ubiquitination and UCHL1 amounts are critical to avoid neurodegenerative deterioration. The UCHL1-AS ncRNA binds in its 5′ Region to the coding transcript’s 5′ Region and causes up-regulation of protein levels without affecting mRNA levels (Carrieri et al., 2012). "
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