The most common age-related neurodegenerative conditions are associated with the build up of various protein aggregates, chemically altered or misfolded proteins that can form solid deposits in and around cells when in that state. These protein aggregates are characterized by the ability to spread and grow, acting as seeds for more aggregation. They include the well known amyloid-β and tau of Alzheimer’s disease, the α-synuclein associated with Parkinson’s disease, and so forth. In recent years researchers have been devoting ever more effort to investigations of a less well known protein aggregate, TDP-43, associated with ALS and frontotemporal lobar degeneration. Today’s open access paper is representative of work taking place to understand TDP-43 aggregates and how and why they form in the aging brain.

The goal of research into protein aggregates is to either find a way to remove them, or to find a way to prevent them from forming in the first place. Protein aggregation is a feature of old people, not young people, despite the fact that the mechanisms that can give rise to aggregation are present throughout life. Thus the damage and change of aging, the rising dysfunction in near all cellular processes, is in some way involved in allowing the presence of protein aggregates to rise to pathological levels. In the research here, the finger is pointed at age-related impairment of the cellular housekeeping systems of the proteasome and autophagy, both of which will break down excess TDP-43 when functioning correctly, at least up until a point.

Partial Failure of Proteostasis Systems Counteracting TDP-43 Aggregates in Neurodegenerative Diseases

Frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative diseases characterized by the mislocalization and cytosolic accumulation of the predominately nuclear TAR DNA-binding protein 43 (TDP-43) in the central nervous system. The presence of TDP-43 neuropathology in ~97% of ALS and ~50% of FTLD cases provides a molecular link, showing both diseases to be on the spectrum of the TDP-43 proteinopathies.

A number of physiological functions are perturbed in FTLD and ALS, including impaired protein homeostasis, RNA dysmetabolism, and reduced nucleocytoplasmic transport of mRNAs and proteins. The cytoplasmic deposition of TDP-43 occurs concomitantly with the depletion of native TDP-43 from the nucleus, causing neurodegeneration in both FTLD-U and ALS by a combination of gain-of-function (GOF) and loss-of-function (LOF) mechanisms. Cytosolic aggregates are known to be intrinsically toxic and able to recruit nuclear TDP-43, exacerbating their deleterious effects by contributing to the nuclear LOF.

In this scenario, it is crucial for neurons to maintain TDP-43 protein homeostasis by the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP). Indeed, a progressive decrease in the efficiency of both protein degradation systems has been reported as a major factor contributing to FTLD-U and ALS onset in aging patients. This hypothesis is also supported by genetic evidence, as many of the mutations associated with FTLD and ALS affect genes involved in UPS- or ALP-mediated degradation. Recent studies showed that the cytosolic accumulation of TDP-43 is turned-over mainly by the UPS, with ALP contributing to its degradation when TDP-43 accumulates as intractable aggregates.

Here we found an early ROS production and caspase-3 activation in murine neuroblastoma N2A cells, following cytosolic transfection with preformed inclusions of human TDP-43 in the absence of any recruitment of the nuclear TDP-43 reservoir. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. We also showed that the UPS and ALP systems are unable to efficiently degrade at least a fraction of the TDP-43 inclusions in neurodegenerative diseases.

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