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protein-aggregation diseases

Saturday 11 February 2006

Aggregation is a complex multi-step process of protein conformational change and accretion. The early species in this process might be most toxic, perhaps through the exposure of buried moieties such as main chain NH and CO groups that could serve as hydrogen bond donors or acceptors in abnormal interactions with other cellular proteins.

Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions. The deposits can be intracellular, extracellular, or both, and there is accumulating evidence that the aggregates may either directly or indirectly cause the pathologic changes. Certain forms of amyloidosis fall in this category of diseases. These disorders are sometimes called proteinopathies or protein-aggregation diseases.

The discovery of protein agregation diseases, however, where multiple proteins sacrifice contacts in the globular native state in favor of inter-chain contacts with neighboring proteins, suggests that some proteins have aggregated states that are thermodynamically equally if not more favorable than the native state.

Many of these agregates have a common morphology named amyloid fibrils, regular fibrillar structures micrometers in length, a few nanometers in diameter.


- Abnormal protein aggregation is a common characteristic of many neurodegenerative diseases of the brain. Filamentous deposits made of the microtubule-associated protein tau constitute a major defining characteristic of several neurodegenerative diseases known as tauopathies.

- In tauopathies, tau aggregation is directly associated with development of neurodegeneration and neuronal death.

Alzheimer disease and Huntington disease

Alzheimer disease (AD) and Huntington disease (HD) are progressive neurodegenerative diseases that are accompanied by insoluble protein aggregates in patient brains. The presence of these obvious pathologic features has suggested that insoluble protein aggregates cause the neuronal dysfunction and ultimate cell death characteristic of both diseases.

Learning and memory disturbances are present in both diseases, although clinical onset of HD in patients is typically defined by motor co-ordination dysfunction. HD is an autosomal dominant disorder caused by the expansion of a trinucleotide CAG repeat in the gene encoding the protein huntingtin. Intracellular HD inclusions are primarily composed of truncated huntingtin protein.

Insoluble aggregated proteins in Alzheimer disease and Huntington disease might not be pathogenic. Human studies have poor correlations between aggregates and clinical disease or pathology in these disorders, whereas mouse models have demonstrated that neuronal loss can occur in the absence of detectable aggregates.

Furthermore, aggregates can exist in the absence of disease pathology in mice or symptoms in humans. Recent research suggests that soluble protein fragments, not insoluble aggregated proteins, are the toxic species in these disorders.

Much research has focused on these insoluble species and the discovery of aggregation inhibitors as possible therapeutic interventions. However, an increasing body of data suggests that these insoluble aggregated proteins are not the disease-causing agent.

The two aggregate hallmarks of AD include extracellular amyloid plaques composed of insoluble fragments of amyloid precursor protein (APP) and intracellular neurofibrillary tangles (NFTs) composed of tau protein (MAPT). Some familial forms of AD are linked to mutations in the APP gene, or genes encoding proteins involved in the processing of APP including presenilin-1 (PSEN1) and 2 (PSEN2).

The first indication that insoluble protein aggregates might not be the primary disease-causing species in HD and AD came from human studies. A variety of mouse models of both HD and AD have enabled the elucidation of the natural history of neuronal dysfunction and death and the temporal relationship to protein aggregation.

In 1999, huntingtin inclusion-specific antibodies revealed that there was little correlation between inclusion burden and the areas of the brain most affected in HD. Only 1–4% of the neurons in the striatum, the brain region predominantly affected in HD, exhibit huntingtin inclusions, compared with a much greater inclusion presence in the cortex, a brain region affected later in the disease.

Initially, the appearance of inclusions near the onset of behavioural changes in the R6/2 model of HD led to the conclusion that inclusions are causative. However, correlation is not causation and studies in full-length huntingtin mouse models of HD revealed that huntingtin inclusions were first detectable months after the initial onset of motor and cognitive dysfunction and neuronal loss.

In Alzheimer disease

In AD, the amount of neuronal amyloid plaques or NFTs in tissue samples demonstrates only a weak correlation with cognitive impairment.

In mouse models of AD, synaptotoxicity, impaired long-term potentiation (LTP) and cognitive impairment occur before the accumulation of amyloid plaques 11 and 12 or NFTs. These data demonstrate that neuronal dysfunction and loss can occur in the absence of detectable insoluble protein species.

Spinocerebellar ataxia type 1 (SCA-1)

In spinocerebellar ataxia type 1 (SCA-1), a trinucleotide repeat disorder similar to HD, expression of an ataxin-1 transgene that has the self-association domain deleted and therefore cannot self-aggregate causes ataxia and neuronal loss in a mouse model in the absence of neuronal inclusions.


- Slow EJ, Graham RK, Hayden MR. To be or not to be toxic: aggregations in Huntington and Alzheimer disease. Trends Genet. 2006 Aug;22(8):408-11. PMID: 16806565

- Ross CA, Poirier MA. Opinion: What is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol. 2005 Nov;6(11):891-8. PMID: 16167052

- Yancopoulou D, Spillantini MG. Tau protein in familial and sporadic diseases. Neuromolecular Med. 2003;4(1-2):37-48. Review. PMID: 14528051

- Trojanowski JQ, Mattson MP. Overview of protein aggregation in single, double, and triple neurodegenerative brain amyloidoses. Neuromolecular Med. 2003;4(1-2):1-6. PMID: 14528048