Walking the tightrope: proteostasis and neurodegenerative disease

Abstract

A characteristic of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), is the aggregation of specific proteins into protein inclusions and/or plaques in degenerating brains. While much of the aggregated protein consists of disease specific proteins, such as amyloid-b, a-synuclein, or superoxide dismutase1 (SOD1), many other proteins are known to aggregate in these disorders. Although the role of protein aggregates in the pathogenesis of neurodegenerative diseases remains unknown, the ubiquitous association of misfolded and aggregated proteins indicates that significant dysfunction in protein homeostasis (proteostasis) occurs in these diseases. Proteostasis is the concept that the integrity of the proteome is in fine balance and requires proteins in a specific conformation, concentration, and location to be functional. In this review, we discuss the role of specific mechanisms, both inside and outside cells, which maintain proteostasis, including molecular chaperones, protein degra-

Susceptibility of Mutant SOD1 to Form a Destabilized Monomer Predicts Cellular Aggregation and Toxicity but Not In vitro Aggregation Propensity

“…The variation in cellular aggregation propensity between SOD1 variants could be due to their intrinsic propensity to aggregate, or given that cells actively generate inclusions in a manner thought to represent a quality control compartment (Weisberg et al, 2012; Farrawell et al, 2015), the level of aggregation may represent an ability of a particular variant to evade cellular protein quality control machinery (Yerbury et al, 2013, 2016). To distinguish between these two possibilities, we sought to assess if there was a correlation between aggregation of purified recombinant SOD1 and SOD1-GFP aggregation in cells.…”

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

“…The fact that proteins central to protein degradation are found across these inclusions types points to the impairment of protein degradation as being an important aspect of the loss of protein homeostasis in ALS. The sequestration of vital protein degradation machinery into inclusions may also further exacerbate the loss of protein homeostasis (65). There is evidence that the subsets of motor neurons that are vulnerable to ALS have decreased expression of ubiquitin-proteasome system genes compared with resistant motor neurons (66).…”

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

“…In addition, fibrillar material released into the extracellular space may interact with neighbouring cells and exert toxic effects (25,26,29,30). As such, the formation of amyloid-rich inclusions in cells has been postulated to be a protective mechanism (31,32), since the deposition of mature amyloid fibrils could sequester harmful small aggregates that would otherwise be cytotoxic.…”