Thinking laterally about neurodegenerative proteinopathies

Abstract

Many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and frontotemporal dementia, are proteinopathies that are associated with the aggregation and accumulation of misfolded proteins. While remarkable progress has been made in understanding the triggers of these conditions, several challenges have hampered the translation of preclinical therapies targeting pathways downstream of the initiating proteinopathies. Clinical trials in symptomatic patients using therapies directed toward initiating trigger events have met with little success, prompting concerns that such therapeutics may be of limited efficacy when used in advanced stages of the disease rather than as prophylactics. Herein, we discuss gaps in our understanding of the pathological processes downstream of the trigger and potential strategies to identify common features of the downstream degenerative cascade in multiple CNS proteinopathies, which could potentially lead to the development of common therapeutic targets for multiple disorders.

Figure 1. Modeling neurodegenerative proteinopathies in transgenic rodents has provided preclinical disease models that support therapeutic discovery.

For most human neurodegenerative diseases there are not naturally occurring animal models. By expressing mutant genes associated with various human neurodegenerative diseases, it has been possible to develop models that often are excellent phenocopies of the CNS proteinopathy associated with the human disease. In many cases, but not all, these models also show neurodegenerative phenotypes. The development of transgenic rodent models has been critical for both mechanistic understanding of neurodegenerative diseases and also for the preclinical testing of novel therapeutics. PHF, paired helical filaments.

Figure 2. Schematic of mechanism of possible spread of neurodegenerative proteinopathies and contribution to cellular demise.

In this scheme, initiation of a proteinopathy can trigger a series of events that illicit feedback that contributes to spread of pathology and cellular demise. Danger signals might include DAMPs but also other signals indicative of cellular stress (ATP release, expression of MHC, etc.). Although there is strong evidence that microglia (and possibly astrocytes) may secrete neurotoxic factors, these factors have not been definitively identified in human neurodegenerative proteinopathies. Although most in the field have focused on mechanisms of neuronal decline, it is also important to consider the possibility that proteinopathies might result in functional decline and death of other CNS cells, including microglia, astrocytes, and oligodendrocytes (not shown). Indeed, in multiple system atrophy, oligodendrocytes are the primary cell affected by α-synuclein inclusions (97), and there is evidence for microglial dystrophy in AD (98).

Figure 3. Schematic of the interrelated neurodegenerative proteinopathies.

Diseases are organized in color blocks that indicate their primary proteinaceous aggregate. AD has primary proteinaceous aggregates of both Aβ (yellow) and tau (red) and is therefore designated orange. Diseases are connected to proteinaceous aggregates that can be observed in at least some cases of the disease with lines. AGD, argyrophilic grain disease; CBD, corticobasal degeneration; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; HD, Huntington’s disease; MSA, multiple system atrophy; Perry synd., Perry syndrome; PDC, parkinsonism-dementia complex; PiD, Pick’s disease; PSP, progressive supranuclear palsy; αSyn, α-synuclein.