Amyloid As A Common Theme In Neurodegenerative Parkinsonian Diseases

All About Parkinson's Disease

Parkinson Diseases Handbook By Lianna Marie

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Parkinson's disease (PD) and Alzheimer's disease (AD) may be pathogenically linked by a single common mechanism: the aggregation and deposition of mis-folded proteins (1-3). Indeed, as summarized in Table 1, nearly every major neurodegenerative disease is pathologically characterized by the insidious accumulation of insoluble filamentous aggregates of normally soluble proteins in the central nervous system (CNS) (3). Since these filamentous aggregates show the ultrastructural and tinctorial properties of amyloid (i.e., ~10 nm wide fibrils with crossed-P-pleated sheet structures that stain with congo red, thioflavin-S, or other related dyes), these diseases are appropriately linked together as brain amyloidoses (4). An understanding that PD and other neurodegenerative parkinsonian diseases including cortical basal degeneration (CBD), progressive supranuclear palsy (PSP), and frontal temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) are related brain amyloidoses may permit novel insights into the pathogenesis of these common movement disorders and ultimately may lead to improvements in diagnosis and therapy for these devastating diseases.

PD is one of the most common forms of brain amyloidosis, and is the archetype a-synucleinopathy (4). The discoveries that mutations and duplications in the a-synuclein gene can lead to the accumulation of insoluble filaments of a-synuclein in Lewy bodies and thus can cause PD have provided strong evidence for the role of a-synuclein in PD (5-9). However, a-synuclein is not the only type of brain amyloid seen in PD. Indeed, abnormal aggregates of tau protein are present in PD and other parkinsonian diseases, making tau pathology one of the most widespread forms of brain amyloid (10-15). A pathogenic linkage between tau abnormalities and parkin-sonian neurodegeneration is suggested by three lines of evidence: (i) histopathologic observations—widespread tau pathology is seen in affected brain regions of many parkinsonian neurodegenerative patients (10-15); (ii) genetic linkages— polymorphisms and mutations in the gene for tau have been linked to PD and other parkinsonian neurodegenerative diseases, respectively (16-23); and (iii) experimental data—in vitro paradigms and transgenic mouse models link tau aggregation to par-kinsonian-related abnormalities in the laboratory (24-29). This chapter reviews these lines of evidence that mechanistically link tau abnormalities to parkinsonian neurodegeneration.

TABLE 1 Amyloid in Neurodegenerative Disease

Disease

Microscopic lesion

Location

Aggregated protein

Alzheimers disease

Amyloid plaque

Extracellular

Amyloid-ß (Aß)

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