Abstract
The HERC protein family is one of three subfamilies of Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases. Six HERC genes have been described in humans, two of which encode Large HERC proteins -HERC1 and HERC2- with molecular weights above 520 kDa that are constitutively expressed in the brain. There is a large body of evidence that mutations in these Large HERC genes produce clinical syndromes in which key neurodevelopmental events are altered, resulting in intellectual disability and other neurological disorders like epileptic seizures, dementia and/or signs of autism. In line with these consequences in humans, two mice carrying mutations in the Large HERC genes have been studied quite intensely: the tambaleante mutant for Herc1 and the Herc2+/530 mutant for Herc2. In both these mutant mice there are clear signs that autophagy is dysregulated, eliciting cerebellar Purkinje cell death and impairing motor control. The tambaleante mouse was the first of these mice to appear and is the best studied, in which the Herc1 mutation elicits: (i) delayed neural transmission in the peripheral nervous system; (ii) impaired learning, memory and motor control; and (iii) altered presynaptic membrane dynamics. In this review, we discuss the information currently available on HERC proteins in the nervous system and their biological activity, the dysregulation of which could explain certain neurodevelopmental syndromes and/or neurodegenerative diseases.
Highlights
The development of nervous system and its homeostasis throughout the lifetime of the individual is the result of the coordinated interplay of many genes that control the differentiation of the distinct re gions of the nervous system [1,2] and, the main processes driving their histogenesis, such as the cell cycle [3], migration [4], neurite outgrowth [5], synaptogenesis [6] and cell death [7,8]
HERC1 mutations have been found in cancer and neuronal disorders, and while somatic mutations have been reported in leukemia, breast cancer and non-melanoma skin cancer [26], germline mutations have been associated to neuronal dis orders (Table 1)
Clinical observations and experimental evidence are accruing regarding the key roles that Large HERC ligases play in neuro development [23,26,99]
Summary
The development of nervous system and its homeostasis throughout the lifetime of the individual is the result of the coordinated interplay of many genes that control the differentiation of the distinct re gions of the nervous system [1,2] and, the main processes driving their histogenesis, such as the cell cycle [3], migration [4], neurite outgrowth [5], synaptogenesis [6] and cell death [7,8]. A vast number of proteins are implicated in these processes, whose correct orchestration depends on maintaining the balance between newly formed proteins and those that age and/or are misfolded In this context, protein degradation is an important part of proteostasis, and the autophagy/lysosome and proteasome pathways are the main mechanisms through which proteins are degraded. Human HERC5 and mouse HERC6 act as E3 ligases for ISG15, a ubiquitin-like protein that is expressed upon stimulation of cells with interferon [20,21,22]. The contribution of the HERC family to nervous system development, function and pathologies is discussed
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