Dement Neurocogn Disord.  2012 Jun;11(2):38-52. 10.12779/dnd.2012.11.2.38.

Misfolded Proteins in Neurodegenerative Dementias: Molecular Mechanisms

• Yang HD
• Ho DH
• Yi MJ
• Seol W
• Kim SY

• KMID: 2172233
• DOI: http://doi.org/10.12779/dnd.2012.11.2.38

Abstract

During recent years, there has been remarkable progress with respect to the identification of molecular mechanisms and underlying pathology of neurodegenerative dementias. The latest evidence indicates that a common cause and pathological mechanism of diverse neurodegenerative dementias can be found in the increased production, misfolding, aggregation, and accumulation of specific proteins such as beta-amyloid, tau protein, alpha-synuclein, prion protein, polyglutamine, transactive response DNA-binding protein (TARDBP or TDP-43), or fused in sarcoma (FUS). The conformational variants of these proteins range from small oligomers to the characteristic pathologic inclusions. However, it is noteworthy that a certain pathology can be a hallmark of a certain dementia, but there is a substantial overlap between different pathologies and different types of dementias. In this review, molecular mechanisms and pathologies of different neurodegenerative dementias will be summarized from the perspective of proteins rather than from the viewpoint of individual dementias. We will also review recent evidence surrounding these protein misfolding disorders, the role of toxic oligomers, cell-to-cell transmission, and the links between the misfolded proteins, along with the general therapeutic strategies for the protein misfolding disorders.

Keyword

Neurodegenerative disorders; Protein misfolding disorders; Dementia

MeSH Terms

alpha-Synuclein
Dementia
Neurodegenerative Diseases
Peptides
Proteins
Proteostasis Deficiencies
Sarcoma
tau Proteins
Peptides
Proteins
alpha-Synuclein
tau Proteins

Figure

• 

  Fig. 1 Pathogenesis of protein misfolding diseases. Naïve proteins are misfolded, self-accumulate, and form oligomers, protofibrils, fibrils, and eventually aggregates or inclusions. An imbalance between production, aggregation, and clearance of proteins brings about accumulation of misfolded proteins. The mature forms are more resistant to degradation than the intermediate species. The common toxic effects of the misfolded proteins may include oxidative stress, neuroinflammatory damage, and disturbed neurotransmitter, synaptic, and mitochondrial functions.

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