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PARTNERS IN RESEARCH: CNDR || IOA || UDALL || Penn ADC
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CNDR Conceptual Framework

The hypothesis that diverse neurodegenerative disease arise from "fatal attractions" of brain proteins serves to link the components of CNDR research programs into a unified conceptual framework

Abnormal protein-protein interactions that result in the formation of intracellular and extracellular aggregates of proteinacious fibrils are a common neuropathological feature of several different sporadic and hereditary neurodegenerative diseases. This is exemplified by the intranuclear neuronal inclusions that are formed by the aggregation of mutant proteins harboring abnormally expanded polyglutamine tracts in hereditary tri-nucleotide repeat disorders, the intracytoplasmic neurofibrillary tangles (NFTs), as well as the extracellular amyloid or senile plaques (SPs) in sporadic and familial Alzheimer's disease (AD), and by the prion protein deposits in the brains of patients with a sporadic or genetic form of spongiform encephalopathy. Indeed, increasing evidence suggests that abnormal protein-protein interactions and/or the lesions that result from the aggregation of these proteins could play a mechanistic role in the dysfunction and death of neurons in several common neurodegenerative diseases (see Table below). Moreover, with respect to sporadic AD and FAD, it is clear that these are heterogeneous ends of a disease spectrum that overlaps with a large group of disorders with prominent tau-rich tangle pathology in the brain known as "tauopathies" on the one hand, and those with prominent synuclein-rich inclusion pathology in the brain known as "synucleinopthies" (see Table below). This overlap is striking and underlines the notion of "fatal attractions" among brain proteins as a common mechanistic theme to account for brain degeneration in AD and related neurodegenerative disorders of the elderly.

The diagnostic hallmarks of AD, the most common tauopathy, are numerous fibrillar beta-amyloid SPs in addition to intraneuronal tau-rich NFTs. Because of their prominence in neurodegenerative tauopathies, filamentous tau inclusions were implicated in the onset/progression of AD and related tauopathies even prior to the discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), which include some families previously classified as FAD.

Although Lewy bodies (LBs) are regarded as hallmark intracytoplasmic neuronal inclusions of Parkinson's disease (PD), they also occur commonly in the brains of patients with the typical clinical and pathological features of AD, and these cases are designated as the LB variant of AD (LBVAD). Further, numerous cortical LBs are the defining brain lesions of dementia with LBs (DLB), which is similar to AD clinically, but distinct from AD pathologically because NFTs and SPs are rare or completely absent in DLB brains. Thus, LBVAD also may reflect the co-occurrence of AD and DLB in the same patient.

Recent reports of familial PD kindreds with missense mutations in the alpha-synuclein gene as well as the demonstration that alpha-synuclein is a major component of LBs in sporadic PD, DLB and LBVAD argue that LBs may be made primarily of alpha-synuclein and that disorders with such inclusions are synucleinopthathies. Indeed, wild type alpha-synuclein may aggregate by itself or with other proteins into LBs and dystrophic neurites in the absence of a mutation, as is the case for tau in AD and other sporadic tauopathies. Moreover, it is now clear that filamentous alpha-synuclein-rich LBs occur in >60% of FAD brains due to autosomal dominant genetic missense mutations in Presenilin 1, Presenilin 2 or the beta-amyloid precursor protein genes and in >50% of Down's syndrome (DS) brains. Surprisingly, alpha-synuclein also is a major component of the inclusions in Hallervodren-Spatz disease (H-SD) as well as the filamentous glial cell inclusions (GCIs) in the white matter oligodendroglial cells of multiple system atrophy (MSA) brains. Thus, the accumulation of alpha-synuclein into filamentous inclusions could play a mechanistic role in the pathogenesis of a number of progressive neurological disorders in addition to PD, DLB, DS, FAD, H-SD, LBVAD, sporadic AD and MSA.

Accordingly, the aggregation of brain proteins into potentially toxic lesions (hence the reference to "fatal attractions") is emerging as a common mechanistic theme in a diverse group of neurodegenerative diseases that share an enigmatic symmetry, i.e., missense mutations in the gene encoding the disease protein cause a familial variant of the disorder as well as its hallmark brain lesions, but the same brain lesions also can be formed by the corresponding wild type protein in a sporadic form of the disease. Thus, it is likely that clarification of this enigmatic symmetry in any one of these disorders will have a profound impact on understanding the mechanisms that underlie all of these disorders as well as on efforts to develop novel therapies to treat them.

Table of Neurodegenerative Diseases Characterized by Filamentous-Lesions formed from aggregated peptides and proteins