. Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nat Genet. 2002 Nov;32(3):420-5. PubMed.

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  1. Ubiquitin and Synaptic Dysfunction: Ataxic Mice Highlight New Common Themes in Neurologic Disease

    The gene responsible for the neurologic symptoms in ataxia mice has been identified and shown to encode a ubiquitin-specific protease. This new study reveals new linkages among ubiquitination, synapse function, and neurologic disease.

    A final commonality in most neurodegenerative diseases including Alzheimer's disease (AD) is loss of neurons in critical brain areas. However, symptoms of illness often precede detectable neuronal loss, and many neurologic syndromes proceed without appreciable cell death or loss of nervous tissue. In such cases, the underlying deficit is believed to be in how the nerve cells themselves function and communicate at synapses. Indeed, aspects of cognitive impairment in both AD and age-related memory decline have been attributed to synaptic dysfunction.1-10 Yet, uncovering the links among disease genes or risk factors, synapse dysfunction, and pathologic features of neurologic disease remains a formidable challenge. Now, a recent paper in Nature Genetics from the laboratory of Nancy Jenkins reports that the neurologic phenotype of ataxia mutant mice is due to loss of a ubiquitin-specific protease which in turn produces profound synaptic dysfunction.11

    Jenkins and colleagues set their sights on identifying the genetic lesion responsible for the severe tremors and hindlimb paralysis in ataxia mutant mice, a recessive mutation that arose spontaneously and was first described almost 40 years ago.12 Through the laborious process of positional cloning, they mapped the mutation within mouse chromosome 18 to a location near Usp14, a gene which encodes ubiquitin-specific protease 14. Consistent with a loss-of-function mutation, expression of Usp14 mRNA was reduced and altered, and Usp14 protein was completely absent from ataxia mutant mice, due to a large insertion in the Usp14 gene. Interestingly, despite a predominantly neurological phenotype, Usp 14 is expressed in many tissues including brain, raising the possibility that these mice have additional, yet unapparent or subtle, defects in other tissues.

    So what exactly is Usp14? Usp14 exists as a member of a large family of enzymes dedicated to clipping off ubiquitin (Ub) from proteins to which this small 76 amino acid polypeptide has been attached.13 Covalent modification of proteins by Ub is important in controlling myriad cellular processes.14 Addition of Ub in growing chains (termed poly-Ub) serves as a targeting signal for marked proteins to be destroyed by the proteasome, a protein-eating machine which acts as the garbage disposal of cells. On the other hand, addition of a single Ub (termed mono-ubiquitination) regulates protein trafficking and protein activity,15 much like other post-translational protein modifications, including phosphorylation.

    Ub itself is attached to proteins through an isopeptide linkage involving the C-terminal carboxylate of Ub and the epsilon-NH2 group of a lysine side chain of the substrate protein.14 At least three distinct sets of enzymatic activities are involved in transferring Ub to proteins. These include the Ub-activating enzyme E1, Ub-conjugating enzymes (E2) and Ub ligases (E3). In addition, a large number of enzymes (including Usp14) control ubiquitin-dependent events by removing Ub.13,16 These deubiquitinating enzymes (DUBs) release Ub from proteins about to be degraded by the proteasome, recycle monomeric Ub from polymeric Ub chains, edit inappropriately ubiquitinated proteins, and reverse regulatory mono-ubiquitination.13,16 In the case of Usp14, this cleavage is specific for release of Ub from mono-ubiquitinated proteins in vitro.17

    How does loss of Usp14 lead to an ataxia neurologic phenotype? Although the molecular mechanisms are still unknown, Wilson et al. provide an important clue by showing that synaptic transmission is abnormal in the ataxia mutant mice.11 Such a "microscopic" deficit was suggested by the fact that ataxia mutant mice have only subtle anatomical changes in the central nervous system with no detectable pathological lesions of regions of cell loss.12,18 Specifically, Wilson et al. found marked alterations in synaptic transmission at both the neuromuscular junction-which makes good sense given the profound muscle wasting and motor deficits in these animals-and, interestingly, at CA3-CA1 synapses in the hippocampus, a brain region involved in learning and memory. The types of synaptic deficits observed, namely decreased quantal content at the neuromuscular junction and decreased paired-pulse facilitation (PPF) and post-tetanic potentiation (PTP) in CA1 hippocampus suggest that the deficit resides on the presynaptic side of the synapse in the machinery that regulates release of neurotransmitter. This finding is quite interesting in light of recent studies demonstrating crucial roles for presynaptic ubiquitination and deubiquitination in axon guidance and synapse development in insects and nonmammalian vertebrates.19 Together with these previous studies, the results of Wilson et al. highlight a largely unappreciated role for Ub-dependent protein modification in synapse function.

    Although the neurologic phenotype of ataxia mutant mice is not associated with significant neurodegeneration, the findings of Wilson et al. emphasize at least two new and emerging themes of relevance to neurodegenerative diseases, including AD. The first theme is the "sub-pathological" or microscopic dysfunction at the level of neuronal synapses. Just as Wilson et al. find subtle, yet physiologically significant synaptic defects in ataxia mutant mice, recent electrophysiological and behavioral studies support a role for synaptic dysfunction in the early stages of AD.2 For example, mutant mice overexpressing wild-type and mutant APP display disrupted synaptic morphology, altered hippocampal synaptic transmission or plasticity, and impairment of spatial learning, often before amyloid plaque deposition.3-7 In addition, exposure of hippocampal neurons to low concentrations of Aβ peptide fragments in brain slices or in vivo results in marked alterations in long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength at CA1 synapses.1,20-22 More recently, examination of mice expressing presenilin-1 mutations linked to familial Alzheimer's disease (FAD) has demonstrated abnormally sensitized hippocampal LTP.23,24 Such synaptic dysfunction is not only involved in clinical syndromes but also in "normal" age-related memory decline. In fact, altered hippocampal synaptic function provides one of the primary electrophysiological markers for memory deficits during aging.8-10

    A second important theme emerging from the studies of Wilson et al. and others19 is the important role of ubiquitin-dependent mechanisms in synaptic function. The accumulation of ubiquitin conjugates and inclusion bodies containing ubiquitin has long been acknowledged in the pathologic lesions associated with a broad array of chronic neurodegenerative diseases, such as the neurofibrillary tangles of AD, Lewy bodies in both Parkinson's disease and Lewy body dementia, Bunina bodies in amyotrophic lateral sclerosis, and nuclear inclusions in CAG repeat expansion disorders such as Huntington's disease, spinocerebellar ataxias, and spinobulbar muscular atrophy.14,25 More recently, mutations in ubiquitin-modifying enzymes and aberrant ubiquitin-proteasome function have been implicated in Parkinson's, Huntington's, and Alzheimer's disease,25,26 as well as other neurologic syndromes.27,28 Intriguingly, many of the mutated ubiquitin-modifying enzymes (e.g., parkin in certain hereditary forms of Parkinson's disease) or potential targets of ubiquitination are present at synapses and may impact synaptic function.29,30

    In the case of AD, a direct relationship between the ubiquitin system and disease pathogenesis has been strongly suggested by the discovery of a frameshift mutation in the ubiquitin which extends the molecule by 20 amino acids [Ub(+1)] in the brains of AD patients, including those with late-onset nonfamilial disease.31 Polyubiquitin chains formed from Ub(+1) are resistant to deubiquitination, and thus potently inhibit the degradation of polyubiquitinated proteins.32 Such inhibition could, in principle, lead to toxic buildup of ubiquitinated proteins, or perhaps alter ubiquitin-dependent modifications necessary for normal synaptic transmission, thereby producing both late and early aspects of disease symptoms, respectively. Additional distinct ubiquitin-dependent mechanisms in AD may occur via the presenilins (PS1 and PS2), proteins involved in processing amyloid precursor protein (APP) which are mutated in various familial versions of AD. Indeed, both PS1 and PS2 are targeted by the ubiquitin-proteasome system.33,34 Whether these ubiquitin-dependent mechanisms are in turn linked mechanistically to synaptic deficits or cell death associated with AD remains to be clarified, but the above discussed findings along with the new results from Wilson et al. further strengthen the link among aberrant ubiquitin-proteasome function, synaptic defects, and neurodegenerative disease.

    More study is clearly needed. In particular, very little knowledge exists regarding the ubiquitin-related enzymatic machinery at synapses or the synaptic proteins targeted by ubiquitination and deubiquitination. Paramount will be understanding the regulation of these important modifications during normal physiology and disease states. Also important will be deciphering the relationship between ubiquitin-dependent protein turnover and plastic or degenerative change at synapses. In this regard, uncovering the links among neurodegenerative disease genes, the ubiquitin-proteasome system, and synaptic signaling complexes promises to illuminate the mechanisms underlying synapse dysfunction in neurologic disease. By identifying a new role for ubiquitin-dependent mechanisms in the synaptic deficits of ataxic mice, Jenkins and colleagues have taken a steady step forward toward this goal.

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