Thinking laterally about neurodegenerative proteinopathies
Todd E. Golde, … , Benoit I. Giasson, Jada Lewis
Todd E. Golde, … , Benoit I. Giasson, Jada Lewis
Published May 1, 2013
Citation Information: J Clin Invest. 2013;123(5):1847-1855. https://doi.org/10.1172/JCI66029.
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Science in Medicine

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.

Authors

Todd E. Golde, David R. Borchelt, Benoit I. Giasson, Jada Lewis

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Figure 2

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

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Schematic of mechanism of possible spread of neurodegenerative proteinop...
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).