Cellular Transfer of Aggregates on Toxic Fragments

In HD it has been shown that both the aggregates and the fragments can be propagated both within the cell and by cell- to-cell transmission. Transmission is the ability of HTT frag­ments that are expressed in one cell type to spontaneously transfer to an adjacent cell. The transmission of mutant HTT has been demonstrated in mouse models of HD, in HD patients grafted with fetal tissue, in HD patients and in HD stem cells implanted into mouse brains.

Further, when healthy human neurons were transplanted into HD mouse models, these neurons began to accumulate mutant HTT and display altered neuronal morphology. The spread of aggregates could have implications on how the disease progresses during aging and which regions of the brain are most vulnerable to this transmission mechanism.

The exact cellular mechanics for this type of transfer have not yet been elucidated but appears to require the synaptic vesicle fusion machinery or cell surface proteins (Trevino et al., 2012). For Tau, which exhibits similar aggregation and fragment tendencies when mutated in Alz­heimer's disease, the transmission mechanism requires hep­arin sulfate proteoglycans (Holmes et al., 2013). Research is currently progressing to better understand the precise mech­anism used for HTT transmission.

One of the hallmarks of ALS is the progression of the dis­ease, the outward spread of muscle atrophy from a central starting point (Hardiman et al., 2011; Robberecht and Philips, 2013). It has been hypothesized that the propagation of symptoms is due to the propagation of the mutant SOD1 aggregates, both within an individual cell and from one cell to another.

The intracellular concept involves a prion-like trans­mission in which a mutant form of the SOD1 will upon contact with a normal form of SOD1 influence the normal SOD1 into changing its confirmation and folding into a mutant-like confirmation (Munch and Bertolotti, 2011). This is a seeding effect in which one mutant protein will affect many normal proteins, which in turn will change their confirmation and affect other normal proteins (Fernandez-Borges et al., 2013; Munch and Bertolotti, 2011; Munch et al., 2011).

This cascade of events eventually proves toxic for the cell, however this only effects a single cell. A broader question examines if a cell with mutant aggregates can transmit these mutant fragments to a neighboring cell and cause the same cascade event. Several studies have shown that in cell culture the secretion of mutant fragments and aggregates occurs, the neighboring cells in­ternalize these mutant fragments through endocytosis, which then act as 'seeds' converting normal folded proteins into misfolded proteins (Munch and Bertolotti, 2011).

The mechanism for SOD1 secretion is specific for mutant SOD1, which exhibits a gain of function by interacting with chromogranins A and B which lead to its secretion, and eventual transmission to neighboring cells (Urushitani et al., 2006). This progression from cell to cell helps explain the progression of symptoms outward from a local starting point in ALS.