Small Changes, Big Impact

Abstract

Huntington disease (HD) is a neurodegenerative disorder caused by an elongated polyglutamine tract in huntingtin (htt). Htt normally undergoes different posttranslational modifications (PTMs), including phosphorylation, SUMOylation, ubiquitination, acetylation, proteolytic cleavage and palmitoylation. In the presence of the HD mutation, some PTMs are significantly altered and can result in changes in the clinical phenotype. A rate limiting PTM is defined as one which can result in significant effects on the phenotype in animal models. For example the prevention of proteolysis at D586 as well as constitutive phosphorylation at S13 and S16 can obviate the expression of phenotypic features of HD. The enzymes involved in these modifications such as caspase-6, the IκB kinase (IKK) complex and still to be characterized phosphatases therefore represent promising therapeutic targets for HD. Identifying and testing specific modulators of PTMs now constitutes the next big challenge in order to further validate these targets and proceed towards the goal of a mechanism-based treatment for HD. Huntington disease: one mutation, multiple pathwaysHtt is a 350 kDa protein which when mutated by an elongated polyglutamine (polyglutamine) tract (>35) causes HD, which manifests with symptoms that include personality changes, involuntary movement and intellectual decline usually in midadulthood (Novak and Tabrizi 2010). On a cellular level, HD is characterized by neuronal dysfunction initially followed by the loss of medium spiny neurons in the striatum and subsequent more wide-spread damage (Albin and others 1990).Even though its mutant form causes predominantly brain pathology, htt is ubiquitously expressed within and outside the nervous system (Strong and others 1993) and is present in different subcellular compartments including the nucleus, the Golgi complex, mitochondria, microtubules and vesicular structures in neurites and at synapses (Caviston, Ross, Antony, Tokito and Holzbaur 2007;Choo, Johnson, MacDonald, Detloff and Lesort 2004;Hoffner, Kahlem and Djian 2002; Kang and others 2007;McGuire, Rong, Li and Li 2006;Strehlow, Li and Myers 2007). A large variety of htt-interacting proteins have been described with a multitude of functions ranging from endocytosis and vesicle transport to cell signalling, apoptosis and transcriptional regulation. Htt acts as a scaffolding protein bringing together its interaction partners and allowing them to transfer information between cellular compartments (Harjes and Wanker 2003), PTMs are postulated to play a major role in the flexibility of htt's protein-protein interactions and to influence its subcellular localization. Htt protein structure and localization of PTMsThe human Htt protein ( Fig. 1) has a polymorphic glutamine stretch at the N-terminus, adjacent to a proline-rich region which is an important mediator of protein-protein interactions, may regulate turnover of the htt protein and keep the protein in a non- (Bhattacharyya and others 2006;Dehay and Bertolotti 2006; South...

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

“…157, 229 Several PTMs in N17 impact htt function, translocation, aggregation, and the toxicity of mutant htt. 51, 229, 235, 240, 241 …”

“…227, 229, 231, 232, 240, 242, 243 The addition of phosphomimetic mutation at S13 and S16 within full length htt with 97Q expressed in a transgenic mouse model reduced visible htt inclusions within the brain and ameliorated HD–like behavioral phenotypes. 232 Phosphorylation at S13 and S16 can be triggered by ganglioside, GM1, and initiate a protective effect that restores normal motor function in transgenic mice.…”

Pathological Unfoldomics of Uncontrolled Chaos: Intrinsically Disordered Proteins and Human Diseases

“…79 Various PTMs of Htt itself, such as phosphorylation, sumoylation, ubiquitination, acetylation, proteolytic cleavage, and palmitylation, are also significantly altered in Huntington’s disease, resulting in changes in clinical phenotypes. 80 In Alzheimer’s disease (AD), which is a neurodegenerative disorder characterized by the progressive cognitive decline and by accumulation of insoluble aggregates of two proteins in the brain, amyloid- β (A β ) and the microtubule-associated protein τ , A β levels and τ aggregation are impacted by altered sumoylation. 81 Aberrant phosphorylation of the microtubule-associated protein τ is known to be associated with AD pathology and pathogenesis of other neurodegenerative disorders called tauopathies.…”

Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation‐Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6

“…[1] This, combined with the fact that this short N-terminal sequence harbors several residues that are subjected to diverse posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination and sumoylation (Scheme S1-A in the Supporting Information), suggests that PTMs may serve as reversible molecular switches for regulating Htt structure, interactome, cellular properties and toxicity. [2] However, the lack of knowledge about the enzymes involved in regulating these modifications has made it difficult to decipher their role in regulating the function(s) of Htt in health and disease.To address these limitations and enable deciphering of the Nt17 PTM code, our group has pursued the development of semisynthetic strategies that permit site-specific introduction of single or multiple PTMs within Nt17 of Huntingtin exon 1 (Httex1). Recently, we reported a semisynthetic strategy that permits site-specific phosphorylation at T3.…”