Lentiviral-induced Striatal Pathology as a Preclinical Model of Polyglutamine Spinocerebellar Ataxias.

Abstract

Polyglutamine spinocerebellar ataxias are a group of six neurodegenerative diseases caused by a mutation in the trinucleotide CAG tract within the coding region of each causative gene. This mutation leads to an abnormally expanded polyglutamine stretch in the protein, making it prone to aggregation and leading to the formation of intraneuronal inclusions, which are a hallmark of these diseases. The molecular mechanisms underlying the pathogenesis of these diseases are complex and not fully understood. So far, these diseases remain incurable. Understanding molecular mechanisms in vulnerable brain regions is essential for therapeutic development. Flexible, region-specific experimental platforms are needed to rapidly test mechanisms and interventions without the time and cost of generating multiple transgenic lines, even though not addressing selective vulnerability. In recent years, we and others have developed several lentiviral-based models to study the impact of expanded protein expression in specific regions of the brain. These models show neuropathological and behavioral features that mimic some disease features, highlighting their importance in understanding the pathogenesis and in the development of new therapeutic strategies. In this paper, we describe the development of a striatal model using SCA2 as an example. We highlight lentiviral vector development and production, and the stereotaxic injection of the vectors expressing the expanded form of ataxin-2 (the disease-causing protein). Lastly, we characterize two main neuropathological hallmarks: the formation of inclusions and the loss of neuronal markers. By providing a controlled platform that reproduces these key pathological features, this model offers a valuable tool to dissect region-specific mechanisms of neurodegeneration and to evaluate targeted therapeutic interventions.