Misfolded Protein Aggregates: Mechanisms for Disease Transmission

Misfolded Protein Aggregates: Mechanisms for Disease Transmission

By March 30, 2018 No Comments

Originally Posted on Science Direct | 5 May 2011

Misfolded Protein Aggregates Mechanisms for Disease Transmission

Some of the most prevalent human degenerative diseases appear as a result of the misfolded protein aggregates. Compelling evidence suggest that misfolded protein aggregation play an important role in cell dysfunction and tissue damage, leading to the disease. Prion protein (Prion diseases), amyloid-beta (Alzheimer’s disease), alpha-synuclein (Parkinson’s disease), Huntingtin (Huntington’s disease), serum amyloid A (AA amyloidosis) and islet amyloid polypeptide (type 2 diabetes) are some of the proteins that trigger disease when they get misfolded.

The recent understanding of the crucial role of misfolded proteins as well as the structural requirements and mechanism of protein misfolding have raised the possibility that these diseases may be transmissible by self-propagation of the protein misfolding process in a similar way as the infamous prions transmit prion diseases. Future research in this field should aim to clarify this possibility and translate the knowledge of the basic disease mechanisms into development of novel strategies for early diagnosis and efficient treatment.

It is well established that protein misfolding diseases (PMDs), also known as “conformational diseases”, are caused by the misfolding of proteins into B-sheet aggregated structures. This conformation is stabilized by intermolecular interactions, leading to the formation of oligomers, proto-fibrils and fibrils, which then accumulate as amyloid deposits in affected tissues. Aggregates of prion protein (PrPSc) in prion diseases (also known as transmissible spongiform encephalopathies or TSEs), amyloid-beta (AB) in Alzheimer’s disease (AD), islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D) or serum amyloid A (SAA) in secondary amyloidosis accumulate extracellularly. Other misfolded aggregates accumulate intracellularly, such as alpha-synuclein (a-syn) in Parkinson’s disease (PD), superoxide dismutase (SOD) in amyotrophic lateral sclerosis (ALS), tau in Tauopathies or AD, and huntingtin (Htt) in Huntington disease (HD).

Although the presence of misfolded protein aggregates in affected tissues was recognized long ago, their role in the disease etiology remained controversial. Only in the past 10 years misfolded proteins have been widely considered to be the triggering factors in the disease. Perhaps the most compelling pieces of evidence in favor of this view came from genetic studies. Most PMDs mainly arise sporadically, without detectable genetic origins; however, a portion (usually small) of the cases can be inherited. Interestingly, mutations in the genes encoding the protein component of the misfolded aggregates have been shown to be genetically associated with inherited forms of the disease. The familial forms usually have an earlier onset and higher severity than sporadic cases. Mutations in the respective misfolded proteins have been associated with familial forms of many diseases, including AD, TSEs, HD, PD, T2D, ALS and various rarer amyloid-related diseases such as familial amyloid polyneuropathy, cardiac amyloidosis, visceral amyloidosis, cerebral haemorrhage with amyloidosis of the Dutch and Icelandic type, and cerebral amyloidosis of the British and Danish type. The fact that mutations in the gene encoding the misfolded proteins produce inheritable disease is by itself a very strong argument for a crucial role of protein misfolding in the disease.

Other evidence for the important role of protein misfolding came from studies aiming to generate transgenic animal models for PMDs. Insertion of human genes encoding mutant proteins with a high propensity to misfold and aggregate leads to emergence of several pathological and clinical hallmarks of the different diseases. Over-expression of human prion protein transgene in mice generates spontaneous neurodegeneration accompanied by brain vacuolization as happens in natural TSEs. In the AD field, the most common transgenic models over-express the amyloid precursor protein (APP) and/or the presenilin 1 (PS1), both genes associated to familial forms of AD. Transgenic mice expressing human mutated APP show amyloid plaques, cognitive impairment, cell death and related inflammatory processes. Although PS1 transgenic animals do not develop amyloid plaques or related alterations, the presence of this gene accelerates disease alterations in the presence of the APP gene through increasing the concentration or amyloidogenicity of AB.

Over-expression of human IAPP transgene in rodent models leads to beta-cell death and diabetes because of accumulation of oligomeric IAPP, which is toxic for beta-cells. Transgenic mice of HD, expressing human Htt gene with expanded poly-glu repeats show intracellular deposits of Htt, neuronal impairment and motor dysfunction. Human a-syn gene expression in transgenic mice induces some of the hallmarks of PD, as dopaminergic cell loss, Lewy bodies accumulation and motor dysfunction. All these findings suggest that misfolding and aggregation of amyloid proteins play a critical role in the pathology and could be the main cause of conformational diseases.


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