Legal but lethal: functional protein aggregation at the verge of toxicity

Abstract

Many neurodegenerative disorders are linked to irreversible protein aggregation, a process that usually comes along with toxicity and serious cellular damage. However, it is emerging that protein aggregation can also serve for physiological purposes, as impressively shown for prions. While the aggregation of this protein family was initially considered exclusively toxic in mammalians organisms, it is now almost clear that many other proteins adopt prion-like attributes to rationally polymerize into higher order complexes with organized physiologic roles. This implies that cells can tolerate at least in some measure the accumulation of inherently dangerous protein aggregates for functional profit. This review summarizes currently known strategies that living organisms adopt to preserve beneficial aggregation, and to prevent the catastrophic accumulation of toxic aggregates that frequently accompany neurodegeneration.

Autoimmune Responses to Soluble Aggregates of Amyloidogenic Proteins Involved in Neurodegenerative Diseases: Overlapping Aggregation Prone and Autoimmunogenic regions

“…2 ). This observation is consistent with ability of human cells to tolerate protein aggregates for functional benefit 27 .…”

The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria

“…Nevertheless, increasing evidence indicates that the proteins involved in many neurodegenerative disorders, including Alzheimer’s and Parkinson’s, display a prion-like behaviour, exhibiting a cell-to-cell propagation [ 70 ]. In addition, different human proteins containing intrinsically disordered domains with an amino acid composition resembling those of the prion forming domains (PFDs) in yeast prions are being found connected to degenerative disorders [ 71 ]. Many of these disorder-linked PrLD-containing proteins are RNA-binding proteins typically containing one or more RRM domains [ 37 ].…”

“…It was initially found to be a major constituent of the protein aggregates in the spinal cord motor neurons, in the hippocampus and neocortex of ALS or FTLD patients, but it is also present in an aggregated form in other neurodegenerative disorders [ 39 ]. A majority of the mutations linked to ALS or FTLD map into the PrLD, implicating thus this domain in the disease [ 71 ]. HNRPDL is a less studied RNA-binding protein, which shares domain organization with TDP-43 (Figure 1 ), despite its precise three-dimensional structure is unknown.…”

Glycoform-independent prion conversion by highly efficient, cell-based, protein misfolding cyclic amplification

“…This change is based on the self-sustained transfer of a structural information from a protein conformer in the prion state to the same protein in the non-prion conformation, presumably through a seeding-polymerization process. Initially formulated to explain prion diseases pathogenesis in human and animals, the prion concept has gained wider relevance in the regulation of diverse biological process and in the progression of other neurodegenerative disorders such as Alzheimer and Parkinson diseases 1 2 3 . Mammalian prions are primarily formed of macromolecular assemblies of PrP Sc , a misfolded, ß-sheet enriched form of the ubiquitously expressed, α-helix rich, host-encoded prion glycoprotein PrP C .…”