The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases

Abstract

The etiologies of neurodegenerative diseases may be diverse; however, a common pathological denominator is the formation of aberrant protein conformers and the occurrence of pathognomonic proteinaceous deposits. Different approaches coming from neuropathology, genetics, animal modeling and biophysics have established a crucial role of protein misfolding in the pathogenic process. However, there is an ongoing debate about the nature of the harmful proteinaceous species and how toxic conformers selectively damage neuronal populations. Increasing evidence indicates that soluble oligomers are associated with early pathological alterations, and strikingly, oligomeric assemblies of different disease-associated proteins may share common structural features. A major step towards the understanding of mechanisms implicated in neuronal degeneration is the identification of genes, which are responsible for familial variants of neurodegenerative diseases. Studies based on these disease-associated genes illuminated the two faces of protein misfolding in neurodegeneration: a gain of toxic function and a loss of physiological function, which can even occur in combination. Here, we summarize how these two faces of protein misfolding contribute to the pathomechanisms of Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease and prion diseases.

Figure 1

Pathomechanisms in AD (A), FTLD linked to chromosome 17 (B), PD (C) and prion diseases (D). (A) In AD, environmental factors, genetic predisposition and mutations in βAPP and PS can affect the metabolism of Aβ. Initially, small and soluble oligomeric assemblies of Aβ42 are produced, which then cause synaptic dysfunction as well as an induction of the amyloid cascade. Note the ‘shortcut' to tau pathology and FTLD via chromosome 17-linked tau mutations. (B) The major variants of chromosome 17-linked FTLD. On the left panel, FTLD cases with tau-positive inclusions (tauopathies) are described. On the right panel, the tau-negative, ubiquitin-positive cases are shown. (C) In sporadic PD and familial PD there are common pathophysiological alterations, such as oxidative stress, mitochondrial dysfunction and protein misfolding, which ultimately result in the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. (D) In the classical form of prion diseases, conversion of PrP^C to PrP^Sc leads to a neurodegenerative and infectious disorder. The conformational transition can occur spontaneously (sporadic), or can be induced by invading PrP^Sc (acquired) or mutations (inherited). Transgenic mouse models indicated that expression of mutant PrPs can trigger neurodegeneration in the absence of infectious prion propagation; whether such disease entities exist in animals or humans is unknown. PrP^Sc: self-propagating isoform, essential component of infectious prions; CtmPrP: a transmembrane form of PrP with the C-terminus facing the cytosol; cytoPrP: cytosolically localized PrP; PG14PrP: mutant PrP containing a nine octarepeat insertion; PrPΔHD: mutant PrP lacking the internal HD.

Figure 2

Examples for gain- and loss-of-function mechanisms leading to neuronal dysfunction and cell death. red: AD; blue: prion diseases; green: PD; purple: FTLD.