Virginia M. Y. Lee

A Precipitating Role for Truncated α-Synuclein and the Proteasome in α-Synuclein Aggregation IMPLICATIONS FOR PATHOGENESIS OF PARKINSON DISEASE

Parkinson disease and other α-synucleinopathies are characterized by the deposition of intraneuronal α-synuclein (αSyn) inclusions. A significant fraction (about 15%) of αSyn in these pathological structures are truncated forms that have a much higher propensity than the full-length αSyn to form aggregates in vitro. However, little is known about the role of truncated αSyn species in pathogenesis or the means by which they are generated. Here, we have provided an in vitro mechanistic study demonstrating that truncated αSyns induce rapid aggregation of full-length protein at substoichiometric ratios. Co-overexpression of truncated αSyn with full-length protein increases cell vulnerability to oxidative stress in dopaminergic SH-SY5Y cells. These results suggest a precipitating role for truncated αSyn in the pathogenesis of diseases involving αSyn aggregation. In this regard, the A53T mutation found in some cases of familial Parkinson disease exacerbates the accumulation of insoluble αSyns that correlates with the onset of pathology in transgenic mice expressing human αSyn-A53T mutant. The caspase-like activity of the 20 S proteasome produces truncated fragments similar to those found in patients and animal models from degradation of unstructured αSyn. We propose a model in which incomplete degradation of αSyn, especially under overloaded proteasome capacity, produces highly amyloidogenic fragments that rapidly induce the aggregation of full-length protein. These aggregates in turn reduce proteasome activity, leading to further accumulation of fragmented and full-length αSyns, creating a vicious cycle of cytotoxicity. This model has parallels in other neurodegenerative diseases, such as Huntington disease, where coaggregation of poly(Q) fragments with full-length protein has been observed.

Tau and α-Synuclein in Neurodegenerative Diseases

The past 2 yr have been extremely prolific in the area of neurodegenerative research, particularly with regard to diseases involving the proteins tau and synuclein. Tau aggregation in the form of filaments has long been implicated in diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), as well as others. The recent discovery of tau gene mutations in patients afflicted by a heterogeneous disease entity termed fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has provided genetic corroboration for the importance of tau in disease and opens novel avenues of investigation into the nature of tau dysfunctions that lead to the demise of neurons. The discovery of mutations in α-synuclein in familial cases of Parkinson’s disease (PD) has led to the revelation that this protein likely plays a prominent role in the etiology of several sporadic neurodegenerative disorders including PD, dementia with Lewy body (DLB) and multiple system atrophy (MSA), collectively grouped as synucleinopathies. In common with the subset of neurodegenerative diseases known as tauopathies because they are characterized by prominent filamentous tau aggregates in neurons and glia, similar fibrillary inclusions also accumulate in the brains of patients with synucleinopathies, but these inclusions are comprised predominantly of α-synuclein aggregates. In this chapter, the current knowledge of synuclein and tau proteins and their possible aberrant, malevolent role(s) in the onset and/or progression of brain diseases is reviewed.