Intrinsically disordered proteins and their (disordered) proteomes in neurodegenerative disorders.

Abstract

The recent years have witnessed a rise in the number of intrinsically disordered proteins (IDPs), also known as hybrid proteins, which possess both structured domains and biologically important intrinsically disordered protein regions (IDPRs). These proteins challenge the “one sequence—one structure—one function” concept by demonstrating that the lack of stable tertiary and/or secondary structure does not preclude proteins from being biologically active (Wright and Dyson, 1999; Uversky et al., 2000; Dunker et al., 2001; Tompa, 2002; Uversky and Dunker, 2010). Both ordered and disordered/hybrid proteins tend to misfold under certain conditions, and the aggregation that typically accompanies protein misfolding is associated with the pathogenesis of several human diseases, particularly those that originate from the deposition of protein aggregates in a variety of organs and tissues (Kelly, 1998; Bellotti et al., 1999; Dobson, 1999; Uversky et al., 1999a,b; Rochet and Lansbury, 2000; Uversky and Fink, 2004; Gasperini et al., 2012; Moreau and King, 2012; Safar, 2012; Walker and LeVine, 2012; Cuanalo-Contreras et al., 2013; Mulligan and Chakrabartty, 2013; Hipp et al., 2014). Misfolding and aggregation of IDPs/IDPRs are especially common in neurodegeneration (Uversky, 2010, 2014a; Breydo and Uversky, 2011). An incomplete list of human neurodegenerative diseases associated with IDPs/IDPRs is provided below. This list shows that some IDPs are involved in several diseases and that some neurodegenerative diseases are associated with misbehavior of several IDPs/IDPRs. The list includes Alzheimer's disease [AD, where the deposition of amyloid-β, tau-protein, and α-synuclein fragment NAC (Glenner and Wong, 1984; Ueda et al., 1993) takes place]; Niemann-Pick disease type C, subacute sclerosing panencephalitis, argyrophilic grain disease, myotonic dystrophy, and motor neuron disease with neurofibrillary tangles (NFTs) (accumulation of tau-protein in the form of NFTs, Lee et al., 1991); Down's syndrome (nonfilamentous amyloid-β deposits, Wisniewski et al., 1985); Parkinson's disease (PD), dementia with Lewy body (LB), diffuse LB disease, LB variant of AD, multiple system atrophy (MSA), and Hallervorden-Spatz disease [all characterized by the deposition of α-synuclein in a form of LB, or Lewy neurites (LNs), Dev et al., 2003]; amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTD) [both characterized by the presence of the cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43) (Nass et al., 2012; Barmada et al., 2014)]; aberrant accumulation of the wild type and mutated fused in sarcoma/translocated in liposarcoma (FUS/TLS) in the cytosol of voluntary motor neurons in sporadic and familial ALS (Pokrishevsky et al., 2012; Sreedharan and Brown, 2013; Ajroud-Driss and Siddique, 2015); prion diseases (deposition of PrPSC, Prusiner, 2001); and a family of polyQ diseases, a group of neurodegenerative disorders caused by the expansion of GAC trinucleotide repeats that code for polyQ in the gene products (Zoghbi and Orr, 1999).