Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases

Abstract

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts.

Figure 1. Flow chart of study selection

CENTRAL = Central Register of Controlled Trials.

Figure 2. Current model of protein aggregation in Parkinson disease (single disease model)

Abnormal soluble oligomers and fibrils of α-synuclein are directly pathogenic (upper panel). Alternatively or complementarily, secondary molecular changes created after protein aggregation combine with oligomers and fibrils to hasten cell death (lower panel). T-0 = time zero; α-syn = α-synuclein.

Figure 3. Alternative models of protein aggregation in Parkinson disease (multiple disease model)

Abnormal soluble oligomers and fibrils of α-synuclein (α-syn), while not directly pathogenic, act as accelerators of neurodegeneration (“fueling the fire”) due to early pathogenic molecular abnormalities, each representing molecularly distinct diseases (A, model 1). Alternatively, abnormal soluble oligomers and fibrils of α-synuclein aggregate into Lewy bodies as byproducts of earlier pathogenic molecular mechanisms, without directly affecting the neurodegenerative process brought on by each molecular disease (B, model 2). Finally, α-synuclein aggregates into Lewy bodies as a mechanism to protect the neuron from toxic protein species or from the biological dysfunction that may have generated the formation of toxic species, “cooling” progression of cell degeneration under biological stress (C, model 3). Note that each molecularly defined disease has a different time to death; collectively, time to neuronal death is longest in diseases corresponding to model C.