Protein misfolding in neurodegenerative diseases

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Protein misfolding and associated aggregate formation are key pathological features of various neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (PD), amyotrophic lateral sclerosis (ALS), and others (Figure 1). Although both wild-type and mutant proteins may form misfolded protein aggregates, certain genetic mutations give rise to abnormal amino acid sequences that increase the propensity for protein misfolding and aggregate formation [1]. One example is the production of defective amyloid-β (Aβ) protein, linked to AD. Various amyloid precursor protein (APP) mutations drive production of mutant Aβ peptides that oligomerize and induce fibril formation (Figure 1). Overproduction of certain protein products or increased metabolic, oxidative, and inflammatory stress responses may also contribute to protein aggregate formation [2].

Figure 1. Protein misfolding and neurodegeneration. Representative proteins associated with five different proteopathies are shown.

The ER’s unfolded-protein response pathway

Misfolded proteins initiate a set of signals that induce endoplasmic reticulum (ER) stress responses, including the unfolded-protein response (UPR), which protects cells from accumulating aggregated proteins. This elaborate quality-control mechanism regulates protein processing, folding, and trafficking in the ER to prevent the buildup of misfolded proteins. Foldases and molecular chaperones play an essential role in this process. Misfolded proteins are either retained within the ER or degraded through autophagy or the proteasome-dependent ER-associated protein pathway. Dysregulation of the UPR pathway has been associated with various neurodegenerative, metabolic, and inflammatory diseases, as well as with cancer [3]. Accordingly, various UPR proteins are being investigated as potential drug targets for a range of human diseases [3].

The UPR consists of transmembrane stress sensors and downstream transcription factors [4]. Examples of ER membrane proteins acting as stress sensors include inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), protein kinase–like eukaryotic initiation factor 2α kinase (PERK), and activating transcription factor 6 (ATF6). Upon activation, these proteins regulate multiple processes, including the rate of protein production, expression of proteins that aid in protein folding, prevention of protein aggregation, and promotion of retrotranslocation and degradation of proteins produced in the ER [1] (Table 1).

Table 1. Proinflammatory proteins associated with leukocytes of the tumor microenvironment.

Target Function Antibody (Cat. No.)
IRE1 ER-resident protein that regulates the transcription factor XPB1 and acts as a transducer of unfolded protein responses IRE1α antibody, rabbit polyclonal (PA1-16928)
PERK Protein kinase that phosphorylates EIF2α to prevent ER influx of pre-modified proteins PERK antibody, rabbit polyclonal (PA5-15305)
ATF6 Transcription factor that mediates up-regulation of chaperone proteins ATF6 antibody, rabbit polyclonal (PA5-20215)
XPB1 Transcription factor for ER stress-related proteins that regulate ER retrotranslocation and degradation of misfolded proteins XBP1 antibody, monoclonal antibody clone 9B7E5 (MA5-15768)

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  1. Rao RV, Bredesen DE (2004) Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr Opin Cell Biol 16:653–662.
  2. Chen X, Guo C, Kong J (2012) Oxidative stress in neurodegenerative diseases. Neural Regen Res 7:376–385.
  3. Wang S, Kaufman RJ (2012) The impact of the unfolded protein response on human disease. J Cell Biol 197:857–867.
  4. Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15:233–249.

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