Visualization of prion-like transfer in Huntington's disease models

Abstract

Most neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease are hallmarked by aggregate formation of disease-related proteins. In various of these diseases transfer of aggregation-prone proteins between neurons and between neurons and glial cells has been shown, thereby initiating aggregation in neighboring cells and so propagating the disease phenotype. Whereas this prion-like transfer is well studied in Alzheimer's and Parkinson's disease, only a few studies have addressed this potential mechanism in Huntington's disease. Here, we present an overview of in vitro and in vivo methodologies to study release, intercellular transfer and uptake of aggregation-prone protein fragments in Huntington's disease models.

The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases

“…Aggregative tendency, and thereby disease progression, are related to the length of the repeat. Mutant Htt (mHtt) fragments as well as polyQ peptides were also shown, upon uptake, to seed conversion of a soluble Htt reporter in cells ( Jansen et al, 2017 ).…”

Network spread determines severity of degeneration and disconnection in Huntington's disease

“…The spatial distribution of diffusion over time in the brain networks when each of the 82 brain regions are used as starting point of diffusion. However, a number of previous studies have demonstrated that the neurobiological mechanisms underlying trans-neuronal spread is an active process, which may involve synaptic vesicles (seeJansen et al, 2017 for a review). Y-axis shows the correlation values (Pearsons correlation) and x-axis shows time in number of years.…”

“…The network diffusion, used in the current study, models the distribution of pathology in HD as a linear passive diffusion process. However, a number of previous studies have demonstrated that the neurobiological mechanisms underlying trans-neuronal spread is an active process, which may involve synaptic vesicles (seeJansen et al, 2017 for a review). Hence, nonlinear active models will be necessary to better capture the neurobiological mechanisms of the disease spread in HD.…”

Immunotherapies in Huntington's disease and α-Synucleinopathies

“…In recent years, there is accumulating evidence that prionlike propagation of pathogenic proteins from cell-tocell accounts for the progression of pathology in HD and α-synucleinopathies. These prion-like spreading and seeding capacities of pathogenic mHtt and a-Syn (either neuron-to neuron or neuron-to-glia) occur via several mechanisms, including exosomal transfer, synaptic transmission, and glial phagocytosis (47)(48)(49)(50)(51)(52)(53)(54). Cell-to-cell transfer of pathogenic proteins disturbs neuroimmune network, leading to enhanced immune response and inflammation, as in these incurable neurodegenerative proteinopathies.…”