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If theories postulating that pathological proteins associated with neurodegenerative disorders behave similarly to prions were initially viewed with reluctance, it is now well-accepted that this occurs in several disease contexts. Notably, it has been reported that protein misfolding and subsequent prion-like properties can actively participate in neurodegenerative disorders. While this has been demonstrated in multiple cellular and animal model systems related to Alzheimer’s and Parkinson’s diseases, the prion-like properties of the mutant huntingtin protein (mHTT), associated with Huntington’s disease (HD), have only recently been considered to play a role in this pathology, a concept our research group has contributed to extensively. In this review, we summarize the last few years of in vivo research in the field and speculate on the relationship between prion-like events and human HD. By interpreting observations primarily collected in in vivo models, our discussion will aim to discriminate which experimental factors contribute to the most efficient types of prion-like activities of mHTT and which routes of propagation may be more relevant to the human condition. A look back at nearly a decade of experimentation will inform future research and whether therapeutic strategies may emerge from this new knowledge.

Decades of research on the prion protein and its associated diseases have caused a paradigm shift in our understanding of infectious agents. More recent years have been marked by a surge of studies supporting the application of these findings to a broad array of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Here, we present evidence to suggest that Huntington's disease, a monogenic disorder of the central nervous system, shares features with prion disorders and that, it too, may be governed by similar mechanisms. We further posit that these similarities could suggest that, like other common neurodegenerative disorders, sporadic forms of Huntington's disease may exist.

International audience; In recent years, substantial evidence has emerged to suggest that spreading of pathological proteins contributes to disease pathology in numerous neurodegenerative disorders. Work from our laboratory and others have shown that, despite its strictly genetic nature, Huntington's disease (HD) may be another condition in which this mechanism contributes to pathology. In this study, we set out to determine if the mutant huntingtin protein (mHTT) present in post-mortem brain tissue derived from HD patients can induce pathology in mice and/or non-human primates. For this, we performed three distinct sets of experiments where homogenates were injected into the brains of adult a) Wild-type (WT) and b) BACHD mice or c) non-human primates. Neuropathological assessments revealed that, while changes in the endogenous huntingtin were not apparent, mHTT could spread between cellular elements and brain structures. Furthermore, behavioural differences only occurred in the animal model of HD which already overexpressed mHTT. Taken together, our results indicate that mHTT derived from human brains has only a limited capacity to propagate between cells and does not depict prion-like characteristics. This contrasts with recent work demonstrating that other forms of mHTT - such as fibrils of a pathological polyQ length or fibroblasts and induced pluripotent stem cells derived from HD cases - can indeed disseminate disease throughout the brain in a prion-like fashion.

International audience; In order to model various aspects of Huntington's disease (HD) pathology, in particular protein spread, we administered adeno-associated virus (AAV) expressing green fluorescent protein (GFP) or GFP coupled to HTT-Exon1 (19Q or 103Q) to the central nervous system of adult wild-type (WT) mice and non-human primates. All animals underwent behavioral testing and post-mortem analyses to determine the long-term consequences of AAV injection. Both mice and non-human primates demonstrated behavioral changes at 2-3 weeks post-surgery. In mice, these changes were absent after 3 months while in non-human primates, they persisted in the majority of tested animals. Post-mortem analysis revealed that spreading of the aggregates was limited, although the virus did spread between synaptically-connected brain regions. Despite the small degree of spreading, the presence of mHTT generated changes in endogenous huntingtin (HTT) levels in both models. Together, these results suggest that viral expression of mHTTExon1 can induce spreading and seeding of HTT in both mice and non-human primates.

Active and passive immunization have been used to treat human disease for hundreds of years and improvements in technology and knowledge is only increasing the number of therapeutic applications. The current and future use of immunization to treat neurodegenerative diseases are briefly described herein to serve as an introduction to this special issue.

Neurodegenerative disorders emerge from the failure of intricate cellular mechanisms, which ultimately lead to the loss of vulnerable neuronal populations. Research conducted across several laboratories has now provided compelling evidence that pathogenic proteins can also contribute to non-cell autonomous toxicity in several neurodegenerative contexts, including Alzheimer's, Parkinson's, and Huntington's diseases as well as Amyotrophic Lateral Sclerosis. Given the nearly ubiquitous nature of abnormal protein accumulation in such disorders, elucidating the mechanisms and routes underlying these processes is essential to the development of effective treatments. To this end, physiologically relevant human in vitro models are critical to understand the processes surrounding uptake, release and nucleation under physiological or pathological conditions. This review explores the use of human-induced pluripotent stem cells (iPSCs) to study prion-like protein propagation in neurodegenerative diseases, discusses advantages and limitations of this model, and presents emerging technologies that, combined with the use of iPSC-based models, will provide powerful model systems to propel fundamental research forward.

A number of publications have reported that cysteamine has significant therapeutic effects on several aspects of Parkinson's disease (PD)-related pathology but none of these studies have evaluated its impact on pathological forms of α-Synuclein (α-Syn), one of the main hallmarks of PD. We therefore tested the efficacy of cysteamine on the Thy1-α-Syn mouse model which over-expresses full-length human wild-type α-Syn. Two-month (early stage disease) and 6-month old (late stage disease) mice and littermate controls were treated daily with cysteamine (20 mg/kg, i.p.) to assess the protective and restorative properties of this compound. After 6 weeks of treatment, animals were tested using a battery of motor tests. Cysteamine-treated transgenic mice displayed significant improvements in motor performance as compared to saline-treated transgenic littermates. Post-mortem readouts revealed a reduction in fibrillation, phosphorylation and total levels of overexpresed human α-Syn. To determine if such outcomes extended to human cells, the benefits of cysteamine were additionally tested using 6-hydroxydopamine (6-OHDA) treated neurons differentiated from induced pluripotent stem cells (iPSCs) derived from a PD patient harbouring a triplication of the SNCA gene. SNCA neurons treated with cysteamine exhibited significantly more intact/healthy neurites than cells treated with 6-OHDA alone. Additionally, SNCA neurons treated with cysteamine in the absence of 6-OHDA showed a trend towards lower total α-Syn levels. Overall, our in vivo and in vitro findings suggest that cysteamine can act as a disease-modifying molecule by enhancing -the survival of dopaminergic neurons and reducing pathological forms of α-Syn.